General Issues More Specific Drugs and how they work.
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Transcript of General Issues More Specific Drugs and how they work.
General Issues
More Specific Drugs and how they work
Drugs and Drug Abuse
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
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?
drug rewards that happen very soon after abehavior – strong positive reinforcement forthat behavior
ex. prep for heroin injection, crack smoking, etc.
2. To avoid feeling bad (reduce withdrawal) (negative reinforcement)
◦ chemical dependence-
Why do people take drugs?
Often a combination of positive and negative reinforcing effects or transition from positive to negative……
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
- 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.......
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
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 –
4. metabolism (detoxification or breakdown)• how a drug is broken down or made into
inactive forms• mostly done by the liver – via enzymes!
5. excretion (elimination)• how a drug once broken down (or not) is
eliminated from body
• most psychoactive drugs metabolites excreted in urine
tolerance – either decreased effectiveness or potency of a drug
Tolerance, Dependence, Withdrawal, etc……
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
metabolic tolerance –
◦ enzyme induction- enzymes are either better at breaking down drug or liver makes more of them
◦ implications?
Mechanisms for Tolerance
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
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
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?
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?
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……
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?
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……
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?
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
chemical see-saw
drug Change from norm
heroin constipation
chemical see-saw
The brain wants to rebalance the activity
heroin WDdiarrhea
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
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?
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?
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?
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
naturally derived (often from plants)◦ cocaine – comes from the coca plant
synthetically derived (in the lab)◦ amphetamine – synthesized in laboratories
psychoactive drugs
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?
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
Psychological dependence – ◦ very strong for drugs that are either smoked, or
injected IV
What about dependence?
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?
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
CNS◦ seizures◦ intracranial hemorrhages (strokes)◦ cocaine or amphetamine induced psychosis◦ formication
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)
virtually all sedative hypnotic drugs work on the GABA receptor to make GABA bind better to its receptor!
how do they work?
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
http://videosift.com/video/Drunk-Animals-of-Africa-the-longer-version
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
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
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
affects many neurotransmitter systems
inhibits glutamate activity
enhances GABA activity◦R0-15-4513
how does alcohol work in the CNS?
Copyright © Allyn & Bacon 2007
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?
First need to treat acute withdrawal
Then follow up with more long-term strategies◦ pharmacotherapies◦ groups like Alcoholics Anonymous
Treating Alcohol Dependence
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
probably 2nd most commonly used drug in US
Nicotine!
Why do so many people start and continue to smoke when we know there are such significant health risks?
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?
nACh receptors – nicotinic subtype of ACh receptors
How does nicotine exert behavioral effects?
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?
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?
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?
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?
Opioid based drugs◦ heroin, morphine, oxycodone, methadone, etc◦ activate endogenous opiate receptors
treatment often uses substitution therapy◦ methadone ◦ buprenorphine ( )
Pharmacodynamics of Other Drugs
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