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pharmacology
RO Davies

Remember: good 
things happen if you learn the material, study hard, and pass the course 
:)

Pharmacology, however, can bring out the dark side of some people. 
Take Dr. Fluharty - an oasis in the field of neuroscience....ha ha ha. He 
refused to take veterinary pharmacology, and reverted to an 
undifferentiated state [insert amusing photo here].

Anyway. This course 
is one in basic pharmacology and toxicology. mechanisms of drug action. 
NOT a clinical course. Don't tell instructors it isn't clinical enough - 
it isn't supposed to be. Also, it's not tailored to individual needs - 
it's for everyone. You have to learn the general stuff - if you want it 
tailored, do it yourself. Also, it is more important for us to learn this 
than for them to teach it. If you don't learn pharmacokinetics and 
differences b/w giving meds to sick or healthy animals, you'll kill 
animals. This has to be learned. The professors don't have time to teach 
everything - only the most important things. You're going to have to 
learn some stuff on their own. Vets from years past didn't learn this in 
school b/c it wasn't around yet. We'll have to learn about new drugs once 
we're out of school, too. This is a basic science course, and therefore 
is NOT limited to interesting things - much like neuroscience. 
Pharmacokinetics won't be interesting to most people. He will try to make 
it interesting, though. He will not succeed, but will try. Course aims: 
one, to make us smart. That's what teachers do - make students smart. Try 
to make our minds a pleasant place to spend some time. Two, to give us a 
good background in pharmacology and toxicology - get us started. give us 
enough to stand on so we can understand stuff we read in books years from 
now. 

quote: the ultimate goal of the educational system is to shift to 
the individual the goals of pursuing his or her education.

students and 
teachers have a social contract - teachers facilitate students' learning. 
students have to want to be facilitated, want to learn, be prepared to 
learn. requires 100% effort from both parties. if student isn't ready to 
be facilitated, shows up late all the time, does crossword puzzles during 
class, reads Victoria's Secret catalogues - then student isn't ready to 
be facilitated - as far as pharmacology goes, anyway. 

This course is 
divided into mostly lectures, with some cases given which are not on 
exams and therefore are poorly attended. Also some conferences to 
supplement lecture material. Also several review sessions to cover 
material we should already know. there is one laboratory - a field trip 
to Jenkins arboretum in Devon, to learn about poisonous plants.  Some 
material will not be presented in proper order. Faculty - only three 
members - Davies, Fluharty, and Kotlikoff. Fluharty and Kotlikoff are not 
general pharmacologists, and Davies isn't a pharmacologist at all, he 
says.

He says that exams are not a reflection of our knowledge, but they 
serve to get our attention so that we can focus on learning this 
material. exams are not like adult circumcision among aborigines and are 
not meant to weed out the weak. the purpose is to teach us pharmacology. 
there will be four exams. they are not cumulative. they are weighted 
according to number of questions per exam. questions are going to be 
objective - probably multiple choice, although he'll make a definitive 
announcement later. fill ins, true false, etc. 

they have acquired over 
a thousand new questions, btw -so do not just study old exams!! if you 
want a 95 study old exams. if you want a 100, study new material. also, 
25% of the lectures come from people who didn't lecture last year so 
don't look at dr aronson's old questions. exams will be proctored and 
stray eyeballs will be immediately thumped. 

grading: if you get a 70 on 
the exams, you must pass the course. in general, the course is curved. 
but if you have a 70 and everyone else has a 100, you still pass.

there 
is a very large, very voluminous handout. Do not lose or destroy the 
handouts. most of the handouts are straight lecture material. Some of it 
is supplemental reading/articles. Those who have handouts will observe a 
piece of red paper - this separates lecture material from supplemental 
material. there are two supplements - one dealing with perianesthetic 
drugs, and one with poisonous plants. these won't be on exams. they are 
supplemental. 

course evaluations should be turned in by everyone. if 
you don't get 90% of the class evaluating, the whole process is 
invalidated. evaluations are read by the faculty. 

RO remarks he's 
willing to meet with small groups of students every few weeks to evaluate 
the course on a realtime basis - we can choose a committee. He's willing 
to change the course, but not on the basis of anonymous evaluations. 


Textbooks - listed in handout. nothing is required - but some are 
recommended. Goodman and Gilman is the best, but is oriented for people. 
It's $90, but still is recommended. There is also a veterinary 
pharmacology text by Adams - less comprehensive, but still good, and has 
a veterinary slant. Is about $125 - vet books are more expensive than med 
books b/c they sell fewer. Then there's a toxicology text - Toxicology by 
Gary Ostweiler. The new toxicology teacher highly recommends this book. 
There is an equivalent book - pharmacology by Evans - the pink book - is 
good, has national board type questions, but has one fatal flaw - it's 
extremely detailed, and you don't need all those details. you may study 
too hard if you get this book. There are two other books which are 
relatively affordable. They are about $40 each - basic and clinical 
pharmacology by someone - human pharm book; and another one called 
Pharmacology by Rang and several other people which is an excellent text. 
If RO had to buy a text, he'd probably buy Rang. Those are general texts 
that you may want to buy. Remember no book is required.

Faculty 
availability - no one has regular office hours. contact info is in the 
handout, however. rodavies@vet.upenn.edu, fluharty@vet.upenn.edu, 
mik@vet.upenn.edu, poppenga@vet.upenn.edu. Also can call Deborah Rone, 
the pharm secretary, at 898-6112. her office is next to RO's in rm 205E 
of the west corridor of the old quadrangle building. 

Those who skipped 
this lecture have missed a lot of really humorous slides and commentary, 
btw.

Be assured that despite RO's presence, this is not a physiology or 
neuro course. They know this is a difficult semester (even if this room 
cools down a bit). We're going to have to learn this, though, so pay 
attention.

Definitions:

Pharmacology: the study of biochemical and 
physiological aspects of drug effects

Drug: hard to define. one 
definition: chemical substances usually applied exogenously, are not 
required for normal biological function, although in the case of hormones 
they may be used as supplements of normal function - anyway, chemical 
substances that interact with living systems and alter bodily function. 
may be beneficial and cure disease, or may cause disease. if you give a 
good drug to the wrong animal you can cause dz. most (not all) drugs are 
effective b/c they effect proteins - they bind to target proteins. 

four 
classes of target proteins: enzymes, carrier molecules (help substances 
cross membranes - NT reuptake systems, etc), ion channels (ligand gated, 
eg ACH receptor, GABA receptor, glutamate receptor), and receptors 
themselves (recognition sites for signalling molecules). 

medical 
pharmacology: a branch of pharmacology dealing with the prevention, 
diagnosis, and treatment of disease. not concerned with why a drug is 
used, but with how it works. 

pharmacokinetics: the way the body handles 
drugs. (effect of body on drugs) deals with route of administration - per 
os, via inhalation, IM, IV; also with how it is absorbed, rate of 
absorption (injection bypasses absorption). also distribution of drugs - 
how drug is distributed to target organ and throughout the body. also 
deals with biotransformation and drug metabolism in liver, lungs, gut, 
where drug may be converted from active to inactive, or inactive to 
active, or to toxic product. also deals with excretion/elimination of 
drug via feces, urine, sweat, exhalation, etc. 

pharmacodynamics: study 
of the effect of drugs on the body and mechanism of action of drugs.


toxicology: branch of pharmacology that deals with undesirable effects of 
chemical substances on living systems.  runs the gamut from individual 
cells, or organelles in cells, to complete ecosystems (ecotoxicology). 


remember: all drugs have multiple actions. as you increase the dose of a 
drug, you will cause that drug to affect targets not meant to be 
affected. once you start affecting nontarget systems, you can start 
causing undesirable side effects and toxicity. we're not playing mae 
west, here - too much of a good thing can be toxic, not wonderful. the 
dose can turn a safe substance into a poison.

quote: administering a 
drug to a patient is analogous to sprinkling salt all over your plate in 
the hope that some will land on the potatoes (and usually it lands 
everywhere but the potatoes, or only a little of it gets on the potatoes, 
and the rest of your food gets all salty at the same time.)

---break---


10-11

Please refer to the "General Principles" page of equations in the 
handout!
These next two hours are a review...although some of it is also 
really a preview for pharmacokinetics. We'll go over some of the concepts 
from physiology and put them into a pharmacological context, and maybe 
learn some new terms. This is just to make sure we're going to know 
what's coming up and what the terms are. Different lecturers cover 
different things and some things fall between the cracks, so we need to 
make sure we're all on the same page.

Again - pharmacodynamics is what a 
drug does to the body. It predicts the concentration of a drug needed to 
achieve a particular effect. What concentration of drug will raise the BP 
10 mmHg? 5 mmHg? concentration-->effect

pharmacokinetics, however, has 
to do with what the body does to the drug - how a certain concentration 
of drug is achieved - how much drug do you have to give to get that 
concentration? what dose is needed? dose--->concentration
route of 
administration, absorption, concentration in ECF, distribution, 
biotransformation, concentration at site of action, metabolites, 
excretion.

concentration links these two concepts - pharmacokinetics and 
pharmacodynamics.
it's important because it is concentration that 
determines the effect, the intensity of drug action. The concentration at 
the site of action is the big thing. now, it's hard to determine the 
concentration of drug at the receptor site, but you can measure the 
concentration of drug in the plasma, so you monitor blood concentrations 
or use a table to figure it out. this is a reasonable index of what's 
going on in the tissues, and it enables you to figure out a time course 
so you know when to give more drug.

so, we'll discuss several concepts 
and some symbol manipulation but not too much re: calculations.

I. 
Conservation of Matter

	A. Concentration-Time curves

as you lose drug, 
you need to add more, so you maintain a constant level of drug in the 
body. What happens if you put a certain amount of drug into the body? 
what happens to those molecules? if you inject a drug into the blood, and 
nothing happens to it, the amount goes up as you inject it and it will 
remain at a steady level forever. But, what happens if it can be 
eliminated from the body after the injection? then, the amount will go up 
as you inject, and then go down as you eliminate it. The important thing 
about this is that most cases we discuss an amount of drug in the blood - 
and if you have a toxic substance in the animal, you can eliminate it by 
exsanguinating the animal, but that won't help the client. these examples 
are talking about amounts, because we're looking at leaking blood out of 
the jar. But, in animals, we discuss concentrations - we don't reduce 
amount, but we reduce concentration of blood. 

Now, if the drug from the 
blood is diffusing into ECF, muscle, other tissues, the concentration in 
blood falls until equilibrium is reached, and then remains constant 
(assuming no elimination). So now, drug is occupying a larger volume but 
at a lower concentration. Amount = concentration x volume. If you have 
the same number of molecules distributed through a larger volume, the 
concentration goes down. realize in this example, we only measure the 
amount of drug in blood.

what if you inject drug into blood and it is 
both distributed and eliminated? amount rises first. then it falls as it 
is distributed, which is a rapid process, and then it continues to fall 
as it is eliminated, but this is slower. this is what pharmacokinetics 
tells us - all about elimination and distribution.



[concentration]
(or 
effect)
                ------------------- toxic level
y

				---
           
*   /    \
	     	-	--------------------- minimum effective concentration             
/           \
         -               -
        /                  \
       
/
      /
     /
	/				

			x	time

note: there is something called a 
first pass effect, which has to do with metabolism of orally administered 
drugs, where it is metabolized either in gut wall, so is never absorbed, 
or in the liver, so that what gets into the systemic circulation is less 
than what you gave, due to this presystemic metabolism since drug first 
passes through liver.

ignoring that...
when you give a drug orally, it 
enters the stomach, and gets absorbed at a certain rate. as it is 
absorbed, it enters the blood, and as it enters the blood the 
concentration rises - most drugs, btw, are absorbed from intestines, not 
the stomach, because of large surface area. it occurs rapidly due to high 
concentration gradient. as it is rapidly absorbed, concentration rises 
fairly linearly. rate of absorption can change due to blood flow, 
inflammation of gut, pH, lots of things. we'll have to know about this 
because if you give a drug too rapidly - eg, if you give IV, 
concentration will rise very rapidly and may go into the toxic zone. * 
now, as drug continues to be absorbed, concentration gradient drops, and 
we see a flattening of the curve. also, drug is distributed to other body 
compartments, leaving the blood, and as blood perfuses organs of 
elimination, drug may be eliminated - so rate of rise no longer is as 
rapid.
at some point, amount going into blood will equal amount leaving 
due to distribution and elimination (flat curve), and then amount in 
blood starts to decrease, because absorption is at a low level while 
distribution and elimination are high. Note that the drug is only 
effective while blood level is above the minimum effective concentration. 
so, you have to give more drug at a certain point, to keep it at an 
effective level. But when do you give it? well, you have to give it 
before you drop beneath the effective level, but if you do it too soon, 
you get into the toxic area. if you wait too long, the drug won't be 
effective. this is a problem with some, but not all drugs. may be a 
problem with antibiotics due to resistance. pharmacokinetics is used to 
help to predict how long the drug will be effective and at what point to 
give the next dose. you must give more drug at the right time, as the 
concentration falls. this is the key thing to remember. 

Slide: 
concentration of a dye in a chamber is set by the rate at which it is 
poured in, and the rate at which it exits. similarly, in the body, 
concentration is set by dose/rate of drug added, and rate of elimination.

	
B. Volume of Distribution (Vd)

Amount = concentration x volume

Vd isn't 
a real volume. it's a volume that a drug would occupy or does occupy, 
either one, if a certain dose is given and a certain concentration is 
found in blood. it's an estimate of the extent to which a drug is 
distributed to compartments other than the blood, and an estimate of the 
drug's uptake by tissue. Volume of distribution is the size of the pool, 
the volume of the pool of body fluids that would be required if the drug 
were distributed equally throughout all parts of the body. it's going to 
depend on the ability of the drug to bind plasma proteins, to cross cell 
membranes, the ionization, the pK, the lipid solubility of the drug, and 
binding in tissue. amount = concentration x volume. amount is the dose. 
so, dose/concentration = volume of distribution.

dose/[drug] = Vd

you 
give a dose, measure the blood concentration, and you have the Vd. Volume 
of distribution of a drug that never leaves the blood is the volume of 
the blood. if you use a drug that escapes and enters other tissues, Vd is 
larger - dose is the same, concentration is lower, Vd is higher. if the 
drug is bound to tissue proteins, and leaves blood almost entirely, you 
get a very large Vd, very small concentration in the blood.  remember, 
you only measure blood - if concentration is low in blood, you say "it 
must be distributed elsewhere over a large volume". If you give an 
organic amine to a cow, it will be distributed, right? cow has a large 
rumen with an acid pH about 5.5-6.5. when the basic amine enters the 
rumen, it picks up a proton, and becomes ionized, so it can no longer 
cross cell membranes. it stays in the rumen, therefore - it's trapped in 
the rumen. now, if you measure the concentration in the blood, it will be 
very very low or zero - so you might think Vd is very large, because you 
have given a large dose, and you can only measure blood levels. so in 
these cases, Vd exceeds the volume of the body - so this is a virtual 
number, not a real number. it's a measure of wide distribution or 
extensive tissue uptake/binding. what's the value of Vd? it explains how 
much drug you have to give to achieve a particular concentration. if Vd 
is high, you have to give a lot of drug to get the concentration up to 
the effective level, because drug is going elsewhere. 

	C. Perfusion 
differences



        |\
conc    | \ --------------- conc in blood
		|     
/------------ conc in brain
		|    /
		|   /
		|  /
		| /
		|/
 

				
time


suppose you give a drug, it's not metabolized, so concentration 
stays constant. now, suppose you perfuse an organ - say the brain. if you 
perfuse the brain, because blood flow is so large, and brain is 
relatively not large, concentration rises rapidly, a lot of drug enters a 
small volume, and as you pull drug out of blood as it enters the brain, 
some of it will leave the blood, enter the brain, and an equilibrium will 
be reached. now, if blood is perfusing a poorly perfused organ like fat, 
it's different. little drug is delivered because flow of blood is poor. 
if this is the case, the concentration of drug in blood will fall more 
and concentration of drug in fat will rise less sharply

my diagram 
sucks, btw. i hope you all wrote it down :). I wrote it down in my notes 
on the "index of chemical rings" page (little personal reminder here).


now, if you perfuse brain and fat, brain concentration goes up, but as 
fat concentration rises, blood concentration falls, so drug leaves brain 
and enters blood, causing brain concentration to fall. so drug is 
distributed to brain and then redistributed to fat. this is called 
"redistribution of drug" (surprise). it's important for some anesthetics 
because drug enters the brain, animal gets anesthetised, blood gradually 
perfuses fat and muscle, blood level drops, brain level drops and at some 
point you drop the concentration in the brain below the effective level. 
anesthetic effects of drugs will be different if an animal has a lot of 
fat or is really thin, therefore. this is especially important with fast 
acting drugs like thiopental, where an animal may exit the surgical plane 
due to redistribution of drug from brain to fat. 

	D. Clearance (CL)

CL 
is a measure of the ability of the body to eliminate a drug. *ability*. 
not the AMOUNT of drug lost, but the *ability* to eliminate the drug. 
it's a quantitative measure. a drug has a certain clearance, 
characterizing the rate of removal of the drug from the body by various 
organs of elimination eg the liver, kidney, lung, skin, bile. it's a 
measure of the rate of disappearance of a substance with respect to the 
concentration. 

amt = conc x vol

amt disappeared = conc x vol


disappearance = vol (of plasma or blood from which drug is removed over 
time)
-------------
conc

so, CL is a volume. why is the concept 
important? because dosage rates should equal elimination rates. to know 
the dose rate, you have to know the elimination rate, and clearance is 
the key factor for determining that. CL says, if you have a handful of 
urine, and that urine has drug in it, CL asks, how did that drug get 
there? how did it get into the urine? 

--he stopped talking here---

	E. 
Extraction ratio ([Ca-Cv]/Ca)



	F. Half-life (tv2) (that's v with a 2 
subscript)

II. Law of Mass Action (to be covered on Wednesday)

	A. 
Drug-receptor complexes (same as enzyme/substrate complexes)
	B. 
Henderson-Hasselbach



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