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