1. Chapter 1: Principles of Pharmacology Psychopharmacology
Psychoactive drug
Before anything else… define the word “drug”
chemicals put into body… foods, medications, herbals,
Pharmacology definition: a chemical substance used in the treatment, cure, prevention, or diagnosis of disease or used to otherwise enhance physical or mental well-being
Introductions – name something that gave you a natural high – caving or rock climbing for the first time; a favorite vacation…
Me – skiing
Pharmacology – study of how drugs interact with body
What is a psychoactive drug? Drug that changes behavior, mood, thinking
Herbals (gingko, St. John’s Wort), recreation (alcohol, caffeine, nicotine), illegal (heroine, cocaine, pot), prescription (Prozac, Valium)
Psychopharmacology – word makes me think of crazy people running around a pharmacy killing people
Really just the study of psychoactive drugs
I will be taking you thru this basic process today, explain some important terms and ideas so that you will understand how drugs cause effects, and why they sometimes fail to cause these effects
Syllabus…
Test your drug knowledge test…
Back to rest of slides…

2. Drug Categories
Stimulants – increase electrical activity in brain and alertness (amphetamine, meth, Ritalin, cocaine, nicotine, caffeine)
Depressants – decrease CNS function thru relaxation and drowsiness (barbiturates, alcohol, benzodiazepines – Valium, marijuana)
Analgesics – decrease sensation of pain, may also decrease CNS function, and (if narcotic) relaxation and sleep (morphine, codeine, heroin, Demerol, methadone, aspirin, acetaminophen, ibuprofen))
Hallucinogens – alter perceptions (mescaline, magic mushrooms, LSD, ecstasy, ketamine, PCP) (last two could also be depressants)
Psychotherapeutics – used only to treat mental disorders, usually not for anything else (prozac, thorazine, lithium, haloperidol, Zoloft)
Distinction not so clear cut though
Nicotine could be seen as stimulant (activates neurons) or depressant (calms people) Ketamine – depressant or hallucinogen

3. Historical Use of a Drug: Opium
Opium Wars
Before talking about what these drugs actually do to our bodies, I thought it would be useful to get some perspective on past drug use, and how certain drug use has been at times lauded as a miracle and other times demonized
Opium has been in use for a long time, Egyptians, Greeks, Chaucer and Shakespeare both mention in it
Opium wars –usually grown in India and surrounding areas
Can be grown in lots of places (China, US), but usually not as potent, and requires a lot of labor-intensive care (need about 18,000 of capsules to make 20 lbs of opium)
16th c. China destroyed naval fleet (used to most powerful in world); then a century later British ships came to China and blockaded Canton, so Emperor opened trade to England (was very resistant to it before – trade situation like Japan and US currently – more Japanese goods going to US than US goods going to Japan – China had no need for what British could give them, but British wanted as much tea as they could get – British had no leverage, nothing to force tea prices down)
Chinese started using opium from India (encouraged by British), Chinese started tradition of smoking it, but Chinese leaders outlawed its use, which meant that it had to smuggled in and no one paid Chinese gov’t taxes on it
British had a good thing going, they imported opium from India to China, which gave them enough money to buy tea to send to England
War started b/c Chinese trying to stop smuggling, British didn’t want that
Two wars actually occurred, both of which China lost

4. Historical Use of a Drug: Opium
Opium use in Europe and US
1880s doctors treated opium like aspirin, gave it to patients for everything from colds to diarrhea, diabetes to insomnia, often cheaper than alcohol – which made sense b/c doctors then did not know much about disease – they were usually treating symptoms of disease, not causes
People with opium addictions not treated as immoral, or as if they had a vice, just as having an unfortunate habit,
Then US started encouraging immigrations of Chinese to Western US to do jobs that US white citizens didn’t want to do (railroads, mining), but lots of discrimination toward Chinese – after jobs were done they were not allowed to joining rest of pop, forced out of rural areas into cities
Some Chinese started opium dens (smoking opium); around this time, economy took a turn for the worse, people started complaining about Chinese stealing jobs from US citizens, US started enacting laws prohibiting opium dens “not because of health concerns as such, but because it was believed that the drug stimulation coolies into working harder than non-smoking whites” –
US claimed opium smoking not “their vice” – Chinese brought it with them, banning also encouraged by stories that dens let Chinese lure white women into white slavery and prostitution
The United States of America during the nineteenth century could quite properly be described as a dope fiend’s paradise. - Edward M. Brecher

5. US drug laws Pure Food and Drug Act – 1906 Harrison Act – 1914
Prohibition (18th amendment) – 1920
Controlled Substances Act – 1970
Pure food and drug act – part of a larger issue – Upton Sinclair had just published The Jungle, in which he described the unsanitary conditions of the meat industry in Chicago,
In addition to regulating food production, Act required medicines to list drugs and amounts
Harrison act – anyone prescribing drugs covered by PFDA had to register and pay an annual tax (had to be a medical doctor, no one else allowed to register), and had to keep records of drugs dispensed
Now, by this time, there were a lot of addicts to drugs like morphine (type of opium), and lot of doctors trying to help people by either giving them the drug or at least keeping them on a maintenance dose (remember, no stigma about drug use at this time)
Gov’t agencies enforcing acts started trying to justify their existence by claiming drugs harmful (often with no evidence), and drug treatment facilities claiming they had 95% success rates (grossly exaggerated), so no one thought anything about requiring people to stop using a “harmful” substance
Drug use became seen as a deviant activity that was associated with crime and poverty
Prohibition – 1920 – no alcohol, encouraged organized crime
Controlled Substances Act – 1970 – schedule of controlled substances, for substances thought to have potential for abuse, created DEA

6. The Life of a Drug in the Body
Route of administration (getting it in)
Absorption/ Distribution (getting to the brain)
Binding (how it works)
Metabolism/Deactivation (stopping it)
Excretion (getting rid of it)
Life of a drug in the body
Route of administration (getting it in)
Absorption/ Distribution (getting to the brain)
Binding (how it works)
Metabolism/Deactivation (stopping it)
Excretion (getting rid of it, getting it out of body)

7. Routes of Administration – Getting the drugs in
First thing, drug has to get into your system
Routes of administration – how drug is given, where it is enters the body (determines how much drug gets to target site – in case of psychoactive drugs, this means the brain, and how quickly)
People come up with some really clever ways of getting it into their bodies
Going to order of most effective to least effective:
Smoking (book talks about inhalation, but this could be two different methods, which have different effects – smoking and snorting)
Drug burns, turns into smoke, gas condenses into droplets (very small), goes all the way to bronchioles in lungs (heavier, larger substances may not get this far); bronchiole is where blood gets oxygenated, from here blood goes to heart and then directly to brain (why do you suppose blood would go directly from heart to brain anyhow?); vary rapid method, 7-10 seconds, but could damage nasal passages/lungs by other particles mixed in with drug; nicotine, methamphetamine
Injecting:
Intravenous (IV) – most rapid and accurate injection method, reaches brain almost instantly, seconds; slower than smoking – why? drug gets into vein, pumped to right side of heart (exact timing here depends on where it is injected), then to lungs, then back to right side of heart, THEN to brain (sometimes this fast response is bad – like if you are allergic), heroine
Slows down even more if drug injected into some place other than a vein (look at right bottom diagram)
Intramuscular (IM) – slower absorption, mins, depends on how fast blood flows to and out of muscles
Snorting (not in diagram)
Inhale powder thru nose, drug crosses into body thru mucus membranes; 3-5 mins - why is this slower than other two methods? Nose is close to brain, after all… drug enters blood vessels near mucus membranes, but then goes back down to heart, then to brain; cocaine
Other direct contact (not in diagram)
Other mucus membranes (eyes, mouth, vagina, anus) or skin
only drugs that are lipid-soluble; eyes: 3-5 mins, skin and other areas: mins; nicotine patch
Oral –
Anything that goes in your mouth and down to your stomach; to be effective, drug has to get to stomach and be dissolved, then reach blood vessels; some of drug gets deactivated by stomach acids and enzymes, then passes to intestines where most of digestion takes place and most of drug is absorbed into blood vessels, blood goes to liver, whose job it is to get rid of substances, so some of drug deactivated here as well – but not all of it obviously, blood goes to heart, then to brain; some drugs resistant to stomach acids and enzymes (insulin cannot do this, so has to be administered another way); mins
(anyone ever go drinking with a friend, they drank just as much as you did, but they threw up shortly after drinking; next morning you have a hangover, they don’t)
(anyone know why drinking alcohol with carbonated liquids will get you tipsy faster? Carbonation forces alcohol out of stomach faster, so more alcohol gets absorbed by intestines)
first-pass effect – drugs absorbed from digestive system go straight to liver before going to general circulation, which tends to deactivate some of the drug
Effect a drug eventually has on the brain depends on how much of drug gets to target receptors (concentration) and how fast it gets there
In this diagram we are really talking about the first two stages of drug in body – routes of administration and absorption
first-pass effect:

8. Method of Administration Affects Blood Concentration
Administration of nicotine by smoking or chewing
Routes of Administration – Getting the drugs in
Method of Administration Affects Blood Concentration
Smoking vs. chewing time course for nicotine
Graph here showing passing of time, vs. blood concentration of a drug
Smoking: there is a rapid peak in concentration of nicotine in blood (lots of nic going directly to brain), followed by rapid decrease
Chewing: (chewing is a cross b/t oral and sniffing - mucus membranes in mouth) – takes longer to get to a peak concentration level, but the peak is present in blood for a lot longer

9. Absorption and Distribution - getting drug to the brain
lipid/water-solubility:
Second step, drug has to be absorbed (how it gets into blood in the first place) and then has to travel to right place
Generally referred to as absorption and distribution – movement of drug from site of administration to blood stream and then to target area
You might notice that we have already been talking about this; remember that even though you can number these steps and put them in order, the boundaries between stages are a bit blurry;
Also important to note, more often than not, stages are occurring simultaneously, not sequentially
Characteristics that will affect absorption:
Most membranes in body made up of two layers of fatty matter called phosolipids – fatty part on inside, parts on outside have a neg charge, fluid on both sides of membrane, inside and outside of cell
Most molecules cannot get thru fatty layer unless they are fat-soluble
Lipid/water solubility: absorption into blood vessels a matter of diffusion; if there is a lot of the drug on one side of a membrane, but little on the other side, there will be a natural push to make drug concentration on both sides equal
If they are fat-soluble, difference in concentration inside and outside of cell will move drug into cell, and level of concentration, or difference in concentration, will determine how fast this happens

10. Absorption and Distribution - getting drug to the brain
lipid/water-solubility HO
Morphine is the active ingredient in opium
Heroin is made from morphine by pouring acetic acid over morphine
Only difference between molecular structure in red; heroin has two extra acetyl groups (Acetyl groups are used to make the natural salicylic acid into the more effective acetylsalicylic acid, or aspirin), which makes it more lipid-soluble than morphine, which means that heroin gets to brain faster, and is more psychoactive
Really the same thing, b/c heroin converted to morphine in brain, but chemical structure of heroin lets it get through membranes faster, so 2-4 times more effective than morphine (when injected) (morphine has hard time getting through BBB), it’s this fast action that helps create euphoric feeling of heroin
Ironically, heroin came about because Bayer was trying to make a med that was more potent pain reliever than morphine without addictive problem
Morphine
Heroin

11. Absorption and Distribution - getting drug to the brain
ionization:
Kind of complicated diagram, only want you to know part of it
Orange line – a membrane, hexagons are molecules of aspirin
Three compartments: blood, stomach, intestine;
idea here is that drug needs to get from right half of diagram to left half
during absorption, some of the drug will tend to separate into different positive or negative parts; the rest of the drug stays whole
Ionization – separation or partial separation of drug into different molecules that have a charge
Basic rule here is, the more ionized a drug is, the harder it is for drug to pass thru lipid membrane
How much drug ionizes depends on two things:
1. how basic/acidic solution is in environment where drug enters (7 neutral, below 7 acidic, above 7 basic/alkaline)
2. basic/acidic property of drug molecule
if drug pH is different from pH of solution it is entering, drug tends to ionize more readily (drug weak acid - <7pH, ionizes more readily in basic solution; less ionized in an acidic solution)
Picture – molecule of aspirin
In stomach, aspirin tends to stay non-ionized (#1) (aspirin weak acid, stomach is acidic, so doesn’t really ionize)
So since non-ionized, tends to be more lipid-soluble (#2) and moves easily into blood
However, blood is neutral (less acidic than stomach), so when aspirin moves into blood, it will be more ionized than it was in stomach and won’t be able to cross back over to stomach again, and will get trapped in blood, unable to move through other membranes
(Ignore intestine)
Another example: SA Indians use curare to kill prey, (blocks receptors that activate muscles, so animal paralyzed, lungs cease working)
They then cook and eat the animal; thing is, the curare is not destroyed by cooking, so why don’t Indians die?
Because curare is highly charged (very ionized, not lipid soluble), so doesn’t pass through membranes of stomach, so it doesn’t hurt them
Curare is only a problem when it gets into your blood stream

12. Absorption and Distribution - getting drug to the brain
blood-brain barrier:
Psychoactive drug molecules tend to be very small- they have to be to reach the brain and get thru blood brain barrier
For LSD, just need 25 micrograms
Average postage stamp – 60,000 micrograms, which is 2,400 doses of LSD
BUT, only 0.01 % of 25 micrograms get to brain
Even though microgram very small, still a large number of molecules in each microgram (2 x 1017 molecules)
Brain very different from rest of body because of blood-brain barrier
Cells in body (including cells that make up capillaries) made of lipids (fats)
Chemicals and other things get into and out of capillaries by either being lipid-soluble, or going thru holes in cells (see left pict)
in brain this is different, all holes are plugged up, only way drug can get thru is by being absorbed thru membrane,
Then another layer of protection, astrocytes surround the capillary, so even if drug gets out of capillaries, but cannot get into brain tissue
Astrocytes control everything that gets into and out of brain tissue, sends in nutrients like glucose, oxygen and amino acids, and takes out waste products like CO2 – brain needs a more stable environment that blood provides, because exact content of fluids makes a huge difference in whether brain functions correctly or not
Some materials can get thru barrier, some cannot
Those that are smaller have an easier time
Leads to bioavailability – amount of drug that is available in the blood to bind at specific target sites; different from blood concentration

13. Binding - how drug works
Drug depots:
Third stage – binding: either drug attaches to a receptor at target site or is stored in places where it is temporarily inactive
Drug depots – areas where drug is bound up, inactive, like muscle and fat
Drug held there until levels of drug decrease in blood, then drug in these areas gradually released and enter blood again
Makes drug effect smaller and delayed (not all of drug getting to site of action immediately)
This seems like a relatively minor part of the process, but it explains a few things that seem confusing at first
a. explains why some people more sensitive to a drug than others, they have differences in binding drugs in depots
b. similar drugs compete for these binding sites, so having a combination of these drugs could lead to overdose (too much of drug gets to action site), which is why doctors tell you not to combine drugs like prozac or valium with other drugs
c. And drug effect prolonged, b/c cannot be metabolized by liver if stuck in fat (this is what happens with THC in pot)
this is why you can sometimes tell if someone has been using a drug long after they took it

14. Binding - how drug works
Receptors:
Receptors located usually on outside of neurons
They have a particular shape that molecules can latch onto
Agonist – helps initiate a process in cell
Antagonist – prevents process in cell
Some important characteristics of receptors
Selective binding – only certain molecules can bind
Temporary binding – molecules bind for a short time, then jump off again, then may rebind again or elsewhere
Receptors can die and new ones are made, which means we could easily change exact number of receptors
Receptors have subtypes – each receptor may accept slightly different molecules, or have slightly different effects

15. Metabolism - stopping drug effect
Excretion - getting drug out of body
Half-life:
drugs destroyed by digestive system, otherwise known as a type of metabolism
Liver deactivates drug (enzymes), kidney sends it out of body in urine (or sometimes goes with feces)
Drug clearance – usually happens exponentially, meaning 50% of drug removed every time interval
Half-life – amount of time it takes for 50% of drug to be removed
Sometimes happens in a few hours, sometimes a few days
first-pass effect – drugs absorbed from digestive system go straight to liver before going to general circulation, which tends to deactivate some of the drug

16. Excretion - getting drug out of body Metabolism - stopping drug effect
advil/aspirin have half-lives of 3-4 hours, so every 3 hrs or so, you will probably have half as much in your blood stream as you did at the beginning of that time period
Aleve, which advertises that it lasts longer, has a half-life of 12 hrs
Half-life really just a way of measuring how long the drug will last, or stay in your system

17. The Life of a Drug in the Body
Route of administration (getting it in)
Absorption/ Distribution (getting to the brain)
Binding (how it works)
Metabolism/Deactivation (stopping it)
Excretion (getting rid of it)

18. Other Important Concepts
Dose–response curve
Dose-response curve – shows graphically the amount of response to a drug of a particular dose
Dose on one axis (how much of drug is given), response on other axis (a particular type of behavior or physiological measurement – could be anything from blood pressure to foot tapping – if you are looking at a dose-response curve, make sure you always know exactly what the response being measured is)
Threshold – smallest dose that produces measurable effect
Maximum response – dose after which no difference in response, assumed that all receptors occupied
Shape of curve: here, before therapeutic dose reached, increased doses change response only a little,
Once therapeutic doses reached, an increase in dosage causes rapid increase in response
But as dosage gets closer to maximum response, increased doses increase response only a little
(ED = half of max dose)

19. Dose–response curves for four analgesic agents
Other Important Concepts
Dose–response curves for four analgesic agents
Comparing different analgesics (dose vs. pain perception)
To have same effect (same amount of pain-relief), requires different doses for different drugs
The lower the dose to have the same effect means that drug is more potent
First three show same curve, which suggests they are working on the same receptors
Main difference is how readily they bind to the receptor
Last one, aspirin, shows different curve, so working on a different receptor
Potency:

20. Comparison effects of a drug
Other Important Concepts
Comparison effects of a drug
Some responses to drugs good, some bad
Overall effectiveness of drug depends on balance of these effects
So here we have a drug that produces three different effects, reduced anxiety, sedation, depressed breathing
Thing to notice here:
Half-way point is when 50% of people will see effect (either good or bad)
Farther curves are from each other means there will be less overlap of effects b/c dose needed to created one effect will be different from dose needed to create 2nd effect (most people will not have respiration effects at a dose that will relieve anxiety, but will be more overlap between anxiety relief and sedation)

21. Other Important Concepts
Effects of Repeated Drug Use
Tolerance:
Is reversible
Not all drug effects show equal tolerance
Types of tolerance
Disposition
Pharmocodynamic
Behavioral
What happens when you take a drug chronically, repeatedly over a period of time?
Tolerance – diminished response to a drug after repeated use
Is reversible
Not all drug effects show equal tolerance, some show rapid tolerance (LSD), others slower tolerance (barbs), others no tolerance (antipsychotics)
Types of tolerance
Disposition – amount of drug available at target tissue decreases, by increased metabolism
Pharmocodynamic – nerve cell function changes with repeated drug use (more or less receptors)
Behavioral – tolerance happens only in a particular environment, caused by learning

22. Effects of Repeated Drug Use
Other Important Concepts
Sensitization
Effects of Repeated Drug Use
What happens when you take a drug chronically, repeatedly over a period of time?
Sensitization
Enhanced response to a drug after repeated use

23. Other Important Concepts
Therapeutic effects
Side effects
Drugs can have multiple effects, on different parts of the body, on different types of cells
Therapeutic effects – drug-receptor interaction that causes desired physical or behavior changes
Side effects – all other effects of the drug
They can change depending on what treatment you are looking for
Amphetamine – ther – alertness, side – loss of appetite (desired effect = staying awake)
Or ther – loss of appetite, side – insomnia (desired effect = weight loss)

24. Drug Development and Testing
Other Important Concepts
Drug Development and Testing
Preclinical studies: petri dishes, nonhuman animals
In vitro – outside a living body, testing in test tubes, etc., trying to out what drugs bind to, what active ingredient is
In animals (in vivo), dose range, lethal doses,
Clinical studies: Humans –
Stage 1 – small group of healthy people (about $10 million)
Stage 2 – small group of people with a disease (about $20 million)
Stage 3 – large groups in different areas (about $45 million)
FDA approval – study results
Only 20% of drugs tested are finally approved