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pharmacology
1/29/98
dr klide

note: exam to cover 
lectures 1 - 23. there IS at least one question on the exam which hasn't 
been covered yet, and it will not count. 

Imidazoline - dr k wrote this 
on the board.

We left off before w/an explanation of cardiovascular 
effects of A2 agonists. 

Imidazoline receptors - all the present A2 
agonists have some affinity for these receptors also.  Two of the 
receptors are named, I1 and I2. I1 is associated with modulation of BP, 
no one knows what I2 was. I1 is interesting wrt A2 agonists b/c it 
appears that analgesic/sedative effects of the A2 agonists are related to 
the A2 receptor effects, and the BP effects are due to imidazole receptor 
interactions. This is interesting if true b/c drugs used to reduce BP are 
commonly used in people with hypertension,and we'd like to do this w/o 
causing sedation. Clonidine, the A2 agonist, causes sedation. We should 
be able to make drugs for sedation and analgesia that are pure A2 
agonists, and drugs to treat hypertension that have high affinity for I1 
receptor and little affinity for A2 receptor.

CNS - analgesia. we talked 
before about NE being involved in systems producing analgesia, but the 
role of NE isn't clear or worked out. Some studies show it decreases 
analgesia, others show it increases analgesia. The only thing clear for 
A2 agonists wrt NE is that A2 agonists do produce some degree of 
analgesia.

Vigilance - the readiness of the animal to react
sedation 
reduces the vigilance while not inducing sleep.
the A2 agonists produce 
this kind of sedation.
you give these tranquilizers to animals and they 
appear markedly sedated - droopy head, droopy ears, in dogs/cats may 
become recumbent. but, they are *rousable,* even spontaneously arousable. 
in the horse, it stands there droopily. you might give A2 agonist to 
sedate horse while doing standing castration under local anesthesia. 
sedative might wear off but horse might not let you know until it was too 
late...
xylazine originally used in lions. lions were not completely 
restrained by them ;) these drugs are useful but not fully reliable for 
restraint.

if you give epi to an individual at some dose it will cause 
ventricular arrhythmias. if you give other drugs like halothane, the dose 
at which the epi causes the arrhythmias is markedly reduced. some A2 
agonists enhance this response. if an animal is very upset and has high 
circulating catecholamines and you give drug that sensitizes myocardium 
to arrhythmogenic effects of catecholamines, you may have a problem. 


smooth muscle contraction we talked about

epidural analgesia - 
activating A2 receptors in cord can induce analgesia. so we've been 
injecting A2 agonists in epidural space to produce analgesia w/o causing 
systemic effects

pulmonary effects: in some spp, A2 agonists cause 
pulmonary edema - rats and sheep esp. mechanism unclear. also causes 
hypoxia. 

MAC - A2 agonists decrease mac of inhaled anesthetics to a 
considerable degree. 

endocrine effects - A2 receptors in pancreas. A2 
agonists inhibit release of insulin, cause hyperglycemia. if you are 
using these drugs to restrain animals for blood sampling, you need to 
think about how it affects the sample.

renal effects: there are A2 and 
A1 receptors in kidney. A1 causes constriction of renal artery. A2 
effects cause a response that produces diuresis. increased urine 
production occurs w/A2 agonist administration. 

repro: some of these A2 
agonist drugs may induce abortion in some spp near end of gestation. most 
clear with xylazine in cattle.

xylazine shares a structural component 
with lidocaine and has some similar toxic effects - twitching and 
seizures. cardiovascular effects as per A2 agonist discussion. xylazine 
in some spp causes vomiting, esp in cats. then cat becomes quiet, 
recumbent, and seemingly restrained but still vigilant. 
endocrine 
effects as described.
cardiovascular effects - some differences 
w/species. initial hypertension and reflex vagal bradycardia. could use 
anticholinergic to tx bradycardia then. 
in horse, the bradycardia is 
responsive to anticholinergics the whole time, and in dog/cat, eventually 
becomes unresponsive to anticholinergics. 
in dog, CO drops, BP rises.
BP 
decreases in rabbits. effects of drugs on rabbits almost always bad. 

respiratory effects - in dogs, cats, horses, no change in ventilation at 
reasonable doses. but if you look at the mms, they will look 
white/purple. this is due to increased vasomotor tone/impaired 
circulation. in sheep/cattle there is decreased pO2/pCO2 - causes hypoxia 
and increased respirations due to decreased ventilation.

behavior: many 
suits have been brought against vets by people hurt by animals given 
xylazine. dogs get grouchy, if you approach them, they will snarl and 
bite. say a large dog is given xylazine to be sedated for eye exam, then 
sent home with warning that he'll be grouchy. owner leaves dog in car 
with child. dog bites child. 

use in cattle - approved in europe but not 
here. still is used here. dose in cattle compared to horse is very 
different - about 1/10th. you don't have to know the dose but should know 
this marked difference. works well in cattle; nothing else works this 
well in cattle. (tranq/sedatives, that is)

xylazine hasn't been commonly 
accepted as a tranquilizer in dogs/cats. is used with ketamine, though. 
in the horse, xylazine has been used a lot, because compared to 
previously available drugs was much more reliable. used by itself or with 
butorphanol for standing chemical restraint. 

ketamine gets horses 
excited but if given reasonable dose of xylazine can use ketamine for 
induction w/o excitation.

detomidine: released in this country for use 
in horses. effects similar to xylazine but dose in cattle is the same as 
in horse. 

medetomidine: released a few mos ago in this country. 
cardiovascular effects same as xylazine, but lasts longer. is available 
and is labelled only for dogs. in europe, labelled for dogs and cats. 
reverse with atipamezole. causes marked bradycardia; it's not clear if 
anticholinergics should be used with it. insert says can pretreat with 
them, but not use them with it or after it. 

alpha antagonists:

alpha 
1: prazosin, labetalol, phenoxybenzamine
alpha 1 and 2: phentolamine, 
tolazoline
alpha 2: yohimbine, atipamezole, tolazoline

yohimbine was the 
first alpha2 antagonist marketed. was around for a while being used to tx 
impotency in men. sometimes this worked, so sometimes people took it at 
parties, but it wasn't that great. now it's marketed as xylazine 
antagonist in dogs. when you first give yohimbine, will first act on the 
periphery and then centrally - so first, vasomotor tone will decrease - 
BP will then drop, there is transient hypotension, then central effects 
kick in and BP comes back up.

tolazoline: labeled as A2 antagonist in 
horse. as it happens, the different A2 antagonists are more useful in 
different spp...sometimes people mix them together.

atipamezole is the 
A2 antagonist marketed to reverse medetomidine. is a more specific A2 
antagonist than the other two above. 

last tranquilizer: reserpine. in 
humans, used to tx hypertension and as a tranquilizer. was found years 
ago and used to modify behaviorin people. it isn't useful as a 
tranquilizer in animals for several reasons, but has been used to study 
sympathetic NS b/c it causes release and depletion of stored 
catecholamines. at appropriate doses can cause chemical sympathectomy. 
veterinarians only get involved with it now if a pet eats its owner's 
pills.


ANESTHESIA:
anesthetic state looks quiet, but is confusing. in 
beginning, we thought drugs would produce effects on a graded scale 
depending on dose, from awake to death. 
first you have sedation, then 
excitement, delirium, surgical plane, then medullary paralysis and death. 
for many years, we thought all anesthetics would fit into this scheme. 
then new drugs came out like enflurane. now there is a new scheme that 
tires to place different drugs into different areas.
many drugs stop at 
the point where part of the patient is excited, and part is anesthetized, 
and if you increase you cause seizures and death. classical anesthetics 
cause excitement, then depression and sleep. but many drugs we use do not 
cause generalized cns depression. 

ether, N2O, and enflurane and 
ketamine, cause a lot of excitement and stimulation but are still useful 
as anesthetics. 
Gamma hydroxybutyrate was tried as an anesthetic, and is 
now a drug of abuse for body builders, because it allegedly causes 
release of growth hormone. also is being abused at parties. it may be 
called GHB, or GBH (grievous bodily harm), or fantasy (not to be confused 
with ecstasy, as it is a stimulant, and fantasy is a depressant)


ketamine and N2O and PCP abuse. ketamine is commonly abused on the 
street, often called special K. 

mechanism of action of 
anesthetics...."and then a miracle occurs..."
we don't know. people 
looked for a single mechanism. meyer overton theory was closest - showed 
that substances that are soluble in olive oil are likely to be potent 
anesthetics. more soluble they were, more likely to be potent anesthetic. 
there's a graph in the handout plotting olive oil solubility of drugs 
compared to their MAC. metofane, halothane, isoflurane, etc. key thing is 
that the drugs soluble in olive oil are more potent than those that are 
less soluble. there is an oil:gas partition coefficient. the partition 
coefficient is the ratio of amount of a drug in two different states - if 
you take a container, put in some olive oil, have some air above it, and 
then cover it, and then inject in some halothane, and let time pass, the 
molecules of halothane will bounce around, and some will be in oil, some 
in air, depending on solubility. the resulting concentrations are 
measured, and their ratio is the oil/gas partition coefficient. can also 
get blood/gas partition coefficient. because of this effect, people were 
lookin at lipids in cell membranes as site of action; now people are 
looking at proteins, and effects on specific receptors. used to look only 
in brain; now also looking in spinal cord. there are definitely effects 
in the spinal cord.

responses of spinal dorsal horn neurons to a 
stimulation can be measured. baseline = 100. then, can expose to drug and 
measure. halothan decreases firing, another drug increases it. both are 
anesthetics. each drug has different effects on each of 5 measurable 
spinal cord responses/reflexes. these are all anesthetics, though. this 
leads one to think that there are multiple sites of action for 
anesthetics. 

there are other experiments that make you think there's a 
single site. one can breed and produce mice that have different 
sensitivity to diazepam - can make them more sensitive or more resistant. 
when you do this and then look at their response to halothane or 
isoflurane, they have the same change in sensitivity to those drgs. 


basically it's a miracle you go to sleep and a miracle you wake up.


barbiturates: old group. many of them. many were used as anesthetics in 
the past, a few still are. derived from barbituric acid. can make 
substitutions to produce more or less potent drugs, drugs that treat or 
cause seizures. substitutions on the C=0 are key. can put an o and make 
oxybarbiturates, or an S and make thiobarbiturates (thiopental) - see 
handout.

these drugs are classed by duration of activity - an old 
classification. 
long lasting, intermediate, short, or ultrashort (newer)


phenobarbital is a long lasting barbiturate - lasts about 12 hrs.

amylbarbital intermediate
pentobarbital is short - 2-4 hrs
less than an 
hour is ultrashort
duration of effect is related to a single dose. some 
of them, esp shorter lasting ones, have extended recovery for reasons 
other than metabolism. in the shorter lasting ones they have several 
mechanisms for recovery - if you give multiple doses you saturate some of 
those mechanisms and prolong your recovery.

part of the mechanism of 
action is related to GABA and Cl- channel. some of effect is enhancing 
GABA change in Cl-, some not. differences in sensitivity of receptor to 
barbiturate. most of the drugs suppress everything, some are not so 
overwhelming, eg phenobarbital - in seizure treatment doses, you will 
inhibit seizure activity but not cause marked sedation. varying degrees 
of sedation are produced in some patients, but generally you can give a 
dose w/o markedly sedating the animal.

these drugs depress activity of 
all excitable tissue - central neural tissue much more sensitive than 
heart, nerves. but this only holds for normal animals. as animals get 
sick, there is greater response in heart, nerves, to the drug. 
cardiovascular effects on healthy animals varies. only consistent thing 
is HR usually goes up with must barbiturates in most spp. BP may not 
change or may transiently drop, CO varies. as animals get sicker, all 
these functions are depressed. so barbiturates are useful in healthy 
aniamls but as animals get sick or debilitated you have to look for other 
drugs. they are all respiratory depressants. given in high enough dose, 
will stop breathing.

for most of the barbiturates, primary use has been 
anesthesia, except the anticonvulsant phenobarbital. usually the drugs 
are given IV for anesthetic, but can give orally, rectally, or IM. onset 
time varies. ultrashort drugs have most rapid onset.

note re: iv drug 
administration: giving a drug IV doesn't mean onset will be rapid. 
thiopental and pentobarbital - thiopental is fat soluble and has short 
onset time given IV. pentobarb isn't/doesn't. if you give pentobarital, 
wait 30-60 sec, and don't see the right depth of anesthesia, do you give 
it more? no. onset for pentobarbital is up to 5 minutes to acheive 
maximum effect. if you don't wait, you end up giving so much that you 
kill the animal.

undesirable affects: apnea, cardiac arrest, effects 
produced by various substances that prolong barbiturate anesthesia - 
often it isn't clear. if you give a barbiturate and animal is waking up 
and you give epi, glucose, or atropine, animal will become 
reanesthetized.  many of barbiturates are irritating to tissues - if 
injected perivascularly will cause severe tissue necrosis. for thiopental 
(most common barbiturate anesthesthetic), necrosis depends on 
concentration. if perivascular injection occurs, inject isotonic fluid in 
area and massage it around, and try to dilute the barbiturate. adding 
lidocaine may also help, b/c it is acid and thiopental is alkaline. 

where do you give IV injections in dog? usually cephalic vein. what 
artery is near there? nothing to worry about. in horse? you give IV drugs 
in jugular - near the carotid artery. if you inject a barbiturate into 
the carotid, it will cause brain necrosis. so, it is very important to be 
sure you know where your needle is.
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