general issues more specific drugs and how they work
TRANSCRIPT
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General Issues
More Specific Drugs and how they work
Drugs and Drug Abuse
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Psychopharmacology – study of drugs and behavior
Drugs and behavior – PSY 459 Clinical Psychopharmacology – PSY 565
Psychoactive drugs – drugs that change the way you feel
All these must reach the brain!
Psychopharmacology
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1. To feel good(positive reinforcement – likely cause DA release!)
psychological dependence
**greatest amount of psychological dependence occurs if the rewarding effects of drugs happen very quickly after behaviors associated with them.
Why do people take psychoactive (particularly illicit) drugs?
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drug rewards that happen very soon after abehavior – strong positive reinforcement forthat behavior
ex. prep for heroin injection, crack smoking, etc.
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2. To avoid feeling bad (reduce withdrawal) (negative reinforcement)
◦ chemical dependence-
Why do people take drugs?
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Often a combination of positive and negative reinforcing effects or transition from positive to negative……
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pharmacokinetics: includes how the drug is taken in
(absorption) how it gets to the brain (distribution) what it does in the brain (nt?;
pharmacodynamics) how it is broken down (metabolism) how it leaves the body (excretion)
Important issues related to how and why we take drugs
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- how a drug is taken into the body……
- for drugs of abuse - the more rapidly the drug gets to the brain – the greater the abuse liability!
pharmacokinetics.......
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oral
injection◦ subcutaneous ◦ intramuscular◦ intravenous - reaches brain in ~ 10 secs
quick response but also most dangerous inhalation - reaches brain in ~8 secs
dermal – absorbed through the skin
buccal or nasal membranes
routes of administration
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1. cocaine – blocks reuptake of monoamine neurotransmitters (most important DA)
2. nicotine◦ acts as an agonist at nicotinic cholinergic
receptors
3. alcohol◦ works on virtually every neurotransmitter
ex of pharmacodynamics –
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4. metabolism (detoxification or breakdown)• how a drug is broken down or made into
inactive forms• mostly done by the liver – via enzymes!
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5. excretion (elimination)• how a drug once broken down (or not) is
eliminated from body
• most psychoactive drugs metabolites excreted in urine
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tolerance – either decreased effectiveness or potency of a drug
Tolerance, Dependence, Withdrawal, etc……
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metabolic tolerance –◦ enzyme induction-
enzymes – speed up a chemical reaction
◦ with repeated exposure, enzymes get better at breaking down drug or liver makes more enzymes
Mechanisms for Tolerance
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metabolic tolerance –
◦ enzyme induction- enzymes are either better at breaking down drug or liver makes more of them
◦ implications?
Mechanisms for Tolerance
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metabolic tolerance –◦ enzyme induction
cross tolerance – tolerance to one drug results in tolerance to other drugs (usually that need similar enzymes for breakdown) ◦ Implications:
Mechanisms for Tolerance
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cross tolerance – tolerance to one drug results in tolerance to other drugs (usually that need similar enzymes for breakdown) ◦ Implications:
◦ Person shows up unconscious at ER and is an alcoholic – given a barbiturate for surgery;
Mechanisms for Tolerance
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tolerance can still occur when the amount of drug reaching the brain/body is unchanged
pharmacodynamic or physiological tolerance –
What if amount of drug reaching brain/body is unchanged?
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pharmacodynamic or physiological tolerance –
“for every action, there is an equal and opposite reaction (in your brain)”
What if amount of drug reaching brain/body is unchanged?
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Use alcohol as an example –
Acutely – alcohol decreases glutamate activity and increases GABA activity
Chronic alcohol -------- brain’s compensatory response?
Ways that the brain may try and compensate……
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upregulation of GLU receptors – ◦ increase the number or sensitivity of glutamate
receptors to compensate for decreased activity and try to get activity back to normal levels….
what happens during alcohol withdrawal?◦ now have too many (or too sensitive) glutamate
receptors – overexcitation, seizures, etc.
How might the brain try and compensate for this change if it is chronic?
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Use alcohol as an example –
Acutely – alcohol decreases glutamate activity and increases GABA activity
Chronic alcohol -------- brain’s compensatory response?
Ways that the brain may try and compensate……
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down regulation of GABA receptors – ◦ to compensate for increased activity and try to
get activity back to normal levels…. – reduce n or sensitivity of GABA receptors
what happens during alcohol withdrawal?◦ now have too few (or too insensitive) GABA
receptors – overexcitation, seizures, etc.
How might the brain try and compensate for this change if it is chronic?
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the exposure of compensatory changes in brain (and body perhaps) likely explain a number of withdrawal symptoms (that are often opposite of the effects that the drug causes)
Explanation for various withdrawal symptoms
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chemical see-saw
drug Change from norm
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heroin constipation
chemical see-saw
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The brain wants to rebalance the activity
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heroin WDdiarrhea
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Drugs taken in the same environment can also display tolerance associated with the conditioned cues
ex. heroin
explanation – compensatory changes in brain in EXPECTATION of drug
Environmental Tolerance
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most treatments do best with both pharmacotherapy and behavioral therapy (of some sort) but the data is still LOUSY!!!
How good are we at treating drug addiction?
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Specific Drugs or Drug Categories In terms of health – Which drugs have the most significant
health effects (for the largest number of people)?
KY issues?
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most treatments do best with both pharmacotherapy and behavioral therapy (of some sort) but the data is still LOUSY!!!
How good are we at treating drug addiction?
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Psychostimulants – increase arousal; sympathetic nervous system◦ cocaine◦ amphetamines
methamphetamine drugs used to treat ADD
Ritalin (methylphenidate) Adderall (mixed salts amphetamine)
Some categories of psychoactive drugs
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naturally derived (often from plants)◦ cocaine – comes from the coca plant
synthetically derived (in the lab)◦ amphetamine – synthesized in laboratories
psychoactive drugs
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Cocaine – block reuptake (DA, NE)◦ block the transporter
amphetamines – block reuptake (actually reverse the transporter) and stimulate release!
methylphenidate – blocks reuptake
how do psychostimulants work?
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stereotypic behavior◦ repetitive behaviors
Appetite suppression◦ weight loss
Possible aggression◦ several descriptions of murder and other
violent offenses attributed to amphetamine intoxication
Behavioral effects of cocaine and/or amphetamine
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Psychological dependence – ◦ very strong for drugs that are either smoked, or
injected IV
What about dependence?
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Psychological dependence – ◦ very strong for drugs that are either smoked, or
injected IV
Physical dependence-◦ do we see a withdrawal syndrome?◦ “cocaine crash” – cause less certain
What about dependence?
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cardiovascular◦ increased risk for CVA◦ cardiac arrhythmia◦ increased blood pressure
respiratory◦ chest pain respiratory complications◦ difficulty breathing
CNS
Medical Side Effects and Consequences of Cocaine and Amphetamine Abuse
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CNS◦ seizures◦ intracranial hemorrhages (strokes)◦ cocaine or amphetamine induced psychosis◦ formication
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produce relaxation, sleep and ultimately (for some sedative hypnotics), unconsciousness and death from respiratory depression if dose is too high
alcohol, barbiturates, benzodiazepenes
Sedative Hypnotics and Anxiolytics (anxiety reducers)
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virtually all sedative hypnotic drugs work on the GABA receptor to make GABA bind better to its receptor!
how do they work?
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First written “recipe” for making beer – about 3000 BC (Egyptians)
fermenting fruit – sugar dissolved in H20 and exposed to air – microorganisms (yeasts) LOVE it
A bit of history about alcohol
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http://videosift.com/video/Drunk-Animals-of-Africa-the-longer-version
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Biphasic Alcohol Effects Scale
Stimulant scale
Elated Talkative
Energized Up
Excited Vigorous
Stimulated
Sedative scale
Inactive Sedated
Down Slow thoughts
Heavy head Sluggish
Difficulty concentrating
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Alcoholism costs the nation $150 Billion / annum
many organ systems are affected including◦ liver- fatty liver and cirrhosis◦ pancreas - pancreatitis◦ heart - cardiomyopathy◦ immune function - compromised◦ endocrine function - altered
Consequences of Alcoholism
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ethanol affects many NT chronic ethanol is not good for CNS
◦ Wernicke’s – thiamine deficiency?◦ Korsakoff’s – more permanent memory deficits
Effects on the CNS
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affects many neurotransmitter systems
inhibits glutamate activity
enhances GABA activity◦R0-15-4513
how does alcohol work in the CNS?
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Copyright © Allyn & Bacon 2007
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Psychological – perhaps some but certainly not as strong as psychostimulants
Physical dependence – absolutely◦ alcohol withdrawal – only withdrawal syndrome
that is potentially LETHAL if not done under medical supervision!!!!
Dependence?
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First need to treat acute withdrawal
Then follow up with more long-term strategies◦ pharmacotherapies◦ groups like Alcoholics Anonymous
Treating Alcohol Dependence
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GABA◦ a down regulation of GABA receptors
Glutamate◦ an upregulation of GLU receptors
Treat with benzodiazepenes during WD ◦ reduces the risk of seizures
Alcohol withdrawal
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probably 2nd most commonly used drug in US
Nicotine!
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Why do so many people start and continue to smoke when we know there are such significant health risks?
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rewarding, pleasurable effects◦ how?
paradoxical effects on arousal◦ biphasic effect with increased attention at lower
doses but decreased anxiety/arousal at higher doses
decreased hunger and resulting weight reduction◦ nt release and increased metabolism because
of sympathetic NS activation
What are the behavioral effects of nicotine?
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nACh receptors – nicotinic subtype of ACh receptors
How does nicotine exert behavioral effects?
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Where are these receptors found?◦ PNS
autonomic ns – so can affect heart rate; blood pressure, etc
muscles – all postsynaptic receptors on muscles are nicotinic!
How does nicotine exert behavioral effects?
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Where are these receptors found?◦ PNS
autonomic ns muscles
biphasic effect◦ low dose – stimulation; high dose – brief
stimulation followed by blockade of transmission
◦ (WHICH IS WHY NICOTINE IS SUCH A POTENT POISON)
How does nicotine exert behavioral effects?
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OH YES!!!!! Psychological Dependence
◦ nicotine produces strong psychological dependence
Physical Dependence◦ for regular smokers – nicotine produces strong
physical dependence
◦ TTFC – time to first cigarette – sometimes used as an indicator of dependence
Does Nicotine Produce Dependence?
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Pharmacotherapy-◦ substitution therapy – provide nicotine via a safer
(and less rewarding route) ◦ intent is to reduce the positive reinforcing effects
AND provide negative reinforcement (ie reducing withdrawal symptoms)
How do we treat nicotine dependence?
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Opioid based drugs◦ heroin, morphine, oxycodone, methadone, etc◦ activate endogenous opiate receptors
treatment often uses substitution therapy◦ methadone ◦ buprenorphine ( )
Pharmacodynamics of Other Drugs
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hallucinogens – a mix of types of drugs
some examples - ◦ LSD like hallucinogens – work on 5HT neurons◦ Amphetamine like hallucinogens – MDMA
(Ecstasy) – seems to have effects on serotonin (in some cases it is neurotoxic to 5HT neurons)
◦ psychedelic anesthetics – PCP; ketamine work on the glutamate receptor