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pharmacology
1/28/98
Dr. Klide

starting at the bottom of 
p 11. still talking about opioids...

Morphine: an agonist at mu, sigma, 
and delta receptors. It's an excellent analgesic, but there are some 
important things to know about it compared to other opioids. differences 
in cardiovascular and behavioral effects. behavioral effects: if given SQ 
or IM, dogs get quiet. If given IV, most dogs will have a marked behavior 
change, becoming extremely aggressive toward anything in their immediate 
environment for 30 - 60 sec, then they get quiet. some people say this is 
due to acute hypotension but that doesn't seem to be true. if you give 
the morphine slowly, it's less likely to occur, if you mix with a tranq, 
still less likely, and if you give the tranq first, still less likely. if 
you give it after a previous dose of morphine, it's not likely to occur, 
or if you give it at the end of anesthesia, it's unlikely to occur. 
morphine is the most sedating of all opioids in the dog. when choosing an 
opioid for chemical restraint, this is a good choice as is hydromorphone. 
when morphine is given to dogs sq or im, the other thing that happens is 
most dogs will vomit and defecate. when given IV, dogs not likely to 
vomit. it's unclear why this difference occurs, most likely when given 
IV, blood level rises rapidly and depresses emetic center. vomition 
occurs with stimulation of CTZ which stimulates emetic center. when level 
rises quickly, emetic center is depressed first. morphine decreases HR 
through vagal inhibition so can tx with anticholinergics. effects on BP 
variable, usually decreases BP a moderate or more amount. variability 
depends on whether or not histamine is released. if histamine is 
released, there is peripheral vasodilation. morphine used as analgesic in 
many spp. may produce excitement in horses, cats, but in appropriate 
doses or with a tranquilizer it's ok.

meperidine: in terms of 
cardiovascular effects, of all the opioids we discuss, this causes the 
most severe drop in BP even in small analgesic doses, when given IV it 
causes marked falls in BP. the BP goes down, CO goes down. HR changes are 
more variable. what is usual response of HR to hypotension? increase. so 
there may be an increase in HR - but also may cause some excitement or 
seizures, which cause tachycardia. meperidine also has some 
anticholinergic properties which will increase the HR. like morphine, 
very likely to cause histamine release. 

oxymorphone: commonly used in 
dogs for many things - preanesthetic, intraanesthetic, postop. one of the 
most sparing opioids on cardiovascular function. very useful for use in 
very sick animals. no histamine release seen in research studies. 


hydromorphone: similar to oxymorphone - consider essentially the same. 
oxymorphone isn't being used as much these days because a) dr klide is 
tired of it and b) hydromorphone costs about 1/2 as much as oxymorphone 
and does the same thing.

methadone: could be used in animals, and was, 
but that usage has markedly decreased, and now it is mainly used to treat 
opioid addiction in humans. it's used in two ways. effects of withdrawal 
from opioids varies with the drug. withdrawal from methadone is slower, 
and least noxious of the opioids. so you switch someone from their drug 
of choice to methadone, and then wean them off the methadone. or, you can 
use it as a maintenance treatment. premise of that is that the people who 
are addicted have opioid deficiencies, and that if you provide the 
opiate, they will function normally. so they give the people methadone. 
the goal is that you give the drug, and then the person can function 
normally.

fentanyl: very very commonly used in anesthetic technique in 
humans and becoming more popular for use in dogs. comes alone and in mix 
with droperidol in a mixture called innovar, used for chemical restraint 
in dogs. fentanyl causes marked bradycardia of vagal origin in dogs, 
easily txd with anticholinergics. was given to horses illegally to try to 
make them run faster when it was first introduced, because it was hard to 
detect its use. now they can detect it. 

there is a whole family of "new 
fentanyls" - sufentanil, alfentanil, remifentanil, carfentanil. released 
for use in humans, used sometimes in anesthesia, not used in animals. 


also re: fentanyl, starting a few years ago, a fentanyl patch was 
marketed, similar to nicotine patch. patch concept is that you put the 
drug in patch, put patch on skin, and it gets absorbed over time. 
fentanyl patch used for people with severe chronic pain. single patch 
lasts several days. used in horses and dogs too.

etorphine - potent 
opioid - used in exotics in this country. cardiovascular effects depend 
on spp - in equines, causes tachycardia and severe hypertension. in dogs, 
bradycardia and hypotension. warning about original package insert - it 
listed species and doses, but the doses in the insert were too high - 
listed the highest doses ever given with survival. it suggested 30 mg for 
zebra, but really the dose should have been 3 mg. then the company that 
made it here stopped making injectable drugs. now, someone else is making 
it, and there is no package insert at all, and they are making a new 
insert. very useful for restraint of exotic herbivores

carfentanil - 
potent opioid used for restraint of exotic herbivores. works well in some 
but not as good as etorphine.

there are many other opioids. heroin is 
one, not marketed here legally but used a lot anyway.many others used as 
oral preps for analgesia or antitussives in humans.

another related 
nonopioid drug is dextromethorpan - robitussin - a common antitussive. it 
is the dextrorotary isomer of an opioid, but it itself doesn't have 
activity at opioid receptors. it isn't supposed to be addictive but is 
quite seriously abused. people on rec.drugs.* talk about this all the 
time, how to concentrate it and take it. the mechanism through which it 
produces antitussive effect is a central effect increasing the threshold 
for coughing, not mediated by opioid receptors. 

opioid antagonists:


nalorphine HCl

naloxone HCl

there are substitutions on the N, removing 
the methyl and putting on longer chains, changing them to antagonists. 
nalorphine was the first one marketed but it is a kappa agonist and a mu 
antagonist, not pure antagonist. naloxone is the most commonly used 
opioid antagonist today - antagonist at mu, kappa, and delta receptors. 
no agonist properties. 

reminders re: antagonists - if the effect you 
want to get rid of was caused by an opioid but not through a receptor 
mechanism, the antagonist won't reverse it. if morphine causes histamine 
release and hypotension, the antagonist won't reverse the hypotension. 
also re: naloxone - duration of effect is shorter than most of the 
commonly used opioids. so you have to watch and see if the effects of the 
opioid return. eg, if you sedate a dog with an opioid, and you reverse it 
with naloxone, and owner walks with dog to go home, dog could have return 
of sedation on the way home. 

it's common to give naloxone IV and give 
another dose subq to get a prolonged effect. 

diprenorphine - antagonist 
that was marketed as antagonist for etorphine by the company that made 
etorphine. that company is gone, this drug is gone now also.the new 
company marketing etorphine isn't marketing this. they are marketing 
naltrexone instead.
naltrexone is a new opioid antagonist marketed as 
antagonist for carfentanil and etorphine. also used in treatment programs 
for opioid addicts to prevent them from getting high if they take an 
opioid. 

opioid agonist/antagonist analgesics:

there is interest in 
this category of drugs for several reasons. one, opioids cause 
respiratory depression. humans more sensitive to this than many other 
spp. this group of drugs causes some respiratory depression, but as you 
increase the dose, the degree of respiratory depression increases less 
rapidly, so respiratory effects plateau, so these drugs seem safer. one 
problem though is that it appears that analgesia also plateaus. the other 
reason for interest is that the drugs weren't federally controlled. 
usually to get opioids you have to fill out all those special forms all 
the time, keep things locked up, it's a lot of extra work and a pain in 
the but. analgesics not controlled in that way are useful. these drugs 
weren't originally controlled, because it was thought that they wouldn't 
cause effects that would make people abuse them - it was thought they 
wouldn't be fun to take. but, they apparently were. these drugs were 
highly abused, and have become controlled

butorphanol,when it came out, 
was not controlled - until 2 mos ago. but abuse was a problem and it is 
now controlled.

pentazocine marketed for use in dogs, horses, and 
people. interest in abuse - high incidence of psychotic reactions and 
hallucinations, so people take this drug, so it became scheduled


butorphanol - very common in veterinary medicine, but there are some 
problems. 
it's used in dogs/cats for analgesia. often given with tranqs 
- different kinds. it is commonly used for restraint of horses at a dose 
below the analgesic dose, given with an alpha2 agonist. in dogs, 
decreases BP and CO and HR; in horses, little or no change in 
cardiovascular function at the doses used. marketed as antitussive for 
dogs. has interesting antiemetic properties. some chemotherapeutic drugs 
like cisplatin cause vomiting, and butorphanol has been useful as an 
antiemetic drug in dogs and ferrets recieving cisplatin. hasn't been 
shown to release histamine in dogs. there are some problems. there are 
differences of opinion re: how useful this is. some think it is a very 
useful analgesic, others think not. Dr Klide thinks not. first: how much 
analgesia does it produce? well, it only seems to cause about a 10% MAC 
reduction even at high doses. this would imply that it isn't that strong 
an analgesic. some people say butorphanol isn't good for bone pain, but 
is good for visceral pain. Dr Klide thinks butorphanol is ok for minor 
pain, and not for severe pain, regardless of the source of the pain. so, 
if analgesic properties are not adequate at the dose you use, then what? 
give more? well, effect plateaus, and in some spp, the dose:effect curve 
is bell shaped. so you peak your analgesic effects and then you give 
more, you might end up with less analgesia. that happens in cats. also, 
if you give butorphanol and it isn't adequate and you need a mu agonist, 
well - butorphanol is a mu antagonist, so it confuses things. this can be 
overcome, but it confuses your dose calculations. 

nalbuphine is 
marketed as analgesic in people, but not used much by us. 

buprenorphine 
- not really part of this group. a partial mu agonist with very high 
affinity for the mu receptor. so it attaches to the receptor, but then 
doesn't produce as great an effect as a full mu agonist would. so if you 
give it to an individual that had no drugs, it will produce some 
analgesia. but if you give it to an animal that has had a mu agonist,it 
will appear to act as a mu antagonist. if you give a dog appropriate dose 
of morphine, then give buprenorphine, it will reverse some of the effect 
of the morphone. it will displace morphine from the receptor because it 
has high receptor affinity, but it will not be a full agonist like 
morphine was. 

apomorphine - chemical modification of morphine, used to 
induce vomiting in dogs and people. it is a dopamine receptor agonist. 
effects not prevented or reversed by opioid antagonists; is inhibited by 
dopamine antagonists like metoclopramide or phenothiazine tranquilizers. 
it has been used in horses b/c it gets them excited and they run faster. 
commonly came in a strange form called a hypodermic tablet. there used to 
be several drugs that came as hypodermic tablets - very soluble in water. 
atropine and morphine came this way. you'd put the tablet in a 
syringe,then draw up some diluent and dissolve the tablet. this wasn't 
sterile, wasn't good. but, since tablet is so soluble, you can put the 
tablet in the conjunctival sac and it will get absorbed quickly.


neuroleptanalgesics: drug mixtures - tranquilizer and opioid. goal : to 
produce better effect than that acheived with either drug alone. can make 
your own mix or use a commercial mix like Innovar-vet.

Innovar-vet = 
fentanyl and droperidol. there isn't anything really special about this 
mix except that someone decided to market it this way. one disadvantage 
of premade mixes is sometimes you want to change the ratio of drugs and 
you can't. this drug came out in late 60s, was fairly commonly used, 
isn't used so much anymore. effects are combination of the two drugs. 
causes bradycardia like fentanyl, and behavior changes associated with 
droperidol.

phenothiazine tranquilizers: they were one of the first 
commercial drugs used to tx mental abberations/psychosis in humans. used 
in animals and people as antiemetics, and are commonly used for chemical 
restraint in animals. acepromazine is most common one available now. used 
to be many more available. 
also used in some other circumstances - one, 
there are conditions in dogs and maybe other spp where ventilation is 
messed up by airway dysfunction, causing animal to be concerned and 
upset. you can give tranquilizer to calm them, and they won't be so 
excited and will breathe better. also used after anesthesia to reduce 
excitatory phase as long as excitement isn't due to pain. 
antipsychotic 
effect seems due to blockade of dopamine 2 receptors. they produce a 
decrease in body temperature usually not a problem but if animal is ill 
or in a cold area this could be a problem. for example, airlines are 
supposed to control temperature of baggage area of planes within a 
certain range, but they don't really do that. if you give one of these 
drugs to an animal and put it on a plane it may not be able to handle the 
temperature extreme. also these drugs depress the pressor response. they 
may produce bizarre motor movements. in humans this occurs after chronic 
use, but in animals it occurs acutely. in horses, they want to trot 
forward after you give them a dose. these drugs are very useful for 
reducing rigidity produced by disease or other drugs. eg, ketamine in 
cats makes them very rigid. if you give phenothiazine tranquilizer with 
it, rigidity is reduced. also can use in patients with tetanus to 
decrease rigidity. use with seizures is more confusing. many drugs cause 
seizures, such as ketamine in nondomestic cats. these tranquilizers stop 
those seizures - but not all kinds of seizures. there are individuals 
with epilepsy - these drugs will decrease the seizure threshold to 
naturally occuring seizures, and so if you give these drugs to an 
epileptic, it may result in a seizure. if a dog comes in that is very 
hard to handle, and is epileptic, but you need to restrain it, 
phenothiazine is probably your choice for restraint, but it might cause a 
seizure. dr klide says he'd probably use the phenothiazine, and then if 
the animal has a seizure, treat it with diazepam. these drugs are also 
used as antiemetics. in the dog, motion does cause emesis through the 
CTZ, so can be useful w/motion sickness.
scopalamine - also useful as 
antiemetic. comes as a patch for people. sometimes, we forget what 
category a drug is in when we use it for a different purpose - antiemetic 
uses for phenothiazines are one such thing. you have to remember the 
effects on BP - if you have an ill animal that is vomiting, you shouldn't 
give a phenothiazine antiemetic because of the vasodilation it will 
cause.


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these tranquilizers are alpha adrenergic 
antagonists - marked alpha 1 antagonists, alpha 2 not really looked at. 
also some dopamine antagonist activity and some antihistamine activity. 
but main thing is these drugs are alpha antagonists and can cause severe 
hypotension esp if sick, hypovolemic, being accelerated (as in a rapid 
elevator).

the penis is special so we'll talk about it. these drugs have 
marked effect on the penis, of primary concern in horse. after giving 
acepromazine to a horse, the penis of the horse is protruded to varying 
extents, up to 100%. it's a dose related effect. the more you give, the 
more it protrudes, and the longer it stays out. the problem is, sometimes 
it doesn't go back and you have to euthanize the animal. this is a 
problem. to say the least.

hypotension from alpha blockade - these drugs 
all cause dose related hypotension. in horses given a phenothiazine 
tranq, systolic and diastolic pressure both drop, and HR increases. if 
hypotension is so severe that you have to treat it, you must remember 
you've used an alpha1 antagonist, and remember what receptors are 
activated by the drug you choose to tx hypotension. epinephrine will 
cause increase in BP - what receptors does epi affect? alpha1 and beta2. 
so, what do you expect to happen? vasoconstriction. the BP should go up. 
beta2 effects would produce vasodilation, though - if you gave a small 
dose of epi, there would be a fall in BP, but if you increase dose, BP 
rises, because of onset of alpha1 agonist effects. in tissues with both 
receptors, alpha effects override beta effects when the dose is adequate. 
then if you wait, as level of epi falls, you get back to low level, and 
beta2 effect returns and you have a return of hypotension. 

say you give 
chlorpromazine (a phenothizine, alpha1 antagonist) - you have 
hypotension. now you give epinephine. you have already blocked the alpha 
receptors with chlorpromazine. all you get are beta effects of epi. more 
hypotension. so you tx hypotension due to alpha1 antagonists by giving 
phenylephrine, a pure alpha1 agonist. this will dire--aaah! a mouse just 
ran across the front of the room!

these also cause splenic dilation - 
spleen gets big and traps blood cells. 
hematocrit drops about 10% in 
normal animals after administration of phenothiazine tranquilizers. so if 
you use these drugs for restraint before you take blood, you have to 
think about this. in sick individuals the effect is even more severe. if 
you start with an anemic animal with PCV 20, and you give one of these 
drugs, PCV can drop to 10, animal can become hypoxic. 

behavioral 
effects: sorry, i missed part of this, watching the mouse run around. 
drug is useful, but if animal is already upset when you give it it isn't 
as useful. all the tranquilizers occasionally cause excitement instead of 
tranquility. the type of excitement is very different b/w different 
categories. phenothiazine tranquilizers very very very rarely produce 
excitement but when they do it is very very very severe. animals will 
attack and chew anything around them, animate or inanimate. dr klide 
relates story of a dog that got some of this drug for a car trip. it 
attacked the owner in the car. the other tranquilizers we'll be getting 
to cause excitement more commonly, to a lesser degree.

dose: dogs/cats - 
dose in insert is about 10x what you need for parenteral dose. oral dose 
is correct. also there is an interaction that was a problem in humans - 
commonly used anthelmintic piperazine, some children had seizures, 
respiratory arrest, and death when given piperazine and phenothiazine 
tranquilizers. 

benzodiazepine tranquilizers: diazepam most commonly 
used. midazolam (versed) used some in animals as well, more in people. 
there's a mix called telazol, which is tiletamine and zolezepam (kinda 
like ketamine and diazepam). another drug that might be used by people is 
going to be discussd.

flunitrazepam - a benzodiazepine tranquilizer


mechanism of action we already learned. there are benzodiazepine 
receptors that influence GABA receptors. the agonists for the receptors 
are these tranquilizers like diazepam, midazolam. there are also 
antagonists - flumazenil - attach to the receptor, don't produce an 
effect. then, there are also inverse agonists - they attach to the 
receptor, do not produce agonist effects or antagonist effect, but 
produce opposite effect of the agonist effects.


agonists effects: 
decreased anxiety, muscle tone, seizure activity, vigilance
inverse 
agonist effect: increases in all of these things

cardiovascular effects: 
some depression. less than phenothiazines. 
produce marked muscle 
relaxation, but not at NMJ. the effect on muscle tone is more central, 
probably a spinal mechanism. 

behavior - when given IV, may cause 
agitation, but relatively mild. 

useful to tx seizures, natural or drug 
induced. useful for txing rigidity produced by ketamine. common to mix 
with ketamine in cats. as animals get sicker, we move away from inhaled 
anesthetics toward injectable drugs that have fewer cardiovascular 
effects - use opioids with benzodiazepines. 

also can decrease needed 
dose of other drugs. many IV anesthetics have side effects or may be very 
expensive. you can give a benzodiazepine to decrease the amount of 
anesthetic you need. diazepam is often used in this way. they are very 
useful for restraint, part of anesthetic in small ruminants. also can be 
used to stimulate the appetite in some animals. 

roofies: date rape 
drug. a benzodiazepam called flunitrazepam, Rohypnol. it's legally 
marketed in other countries for anxiety and as a sleep aid. however, 
people use this drug to try to get people to do things they wouldn't 
otherwise do, and not remember. it's soluble and tasteless. it can be 
added into a drink and will potentiate the effects of alcohol. 
benzodiazepines also produce amnesia. this drug has been smuggled into 
this country since the mid 1990s. in 1995, the government seized 140,000 
tablets so there are probably a lot of them here. there are a lot of web 
sites with information about the drug. dr klide did a study, added some 
diazepam tablets into water and alcohol. he found it didn't dissolve that 
well. 

differences b/w the benzos:
diazepam is most commonly used, but 
not very soluble in water. it is mixed w/propylene glycol in injectable 
form. if mixed w/water or other drugs, might precipitate. if a mixture 
produces a precipitate that is hard and chunky, you should not inject it. 
but, there are degrees of particle size, and rates of solubility, etc. 
the precipitate formed by diazepam is very small, and dissolves in blood. 
if you have a syringe of diazepam and you inject it, it probably 
precipitates in the blood initially until it gets diluted. that's ok. so 
you can mix with opioids despite the precipitate. diazepam may also 
irritate the veins, produce thrombophlebitis. also, duration of activity 
is a concern. consider in humans, the difference in duration b/w diazepam 
and midazolam is marked. diazepam t1/2 =36 hrs, midazolam = 1-2 hrs. in 
humans. but in animals, it's more like 4 and 2 hrs. much less of a 
difference. midazolam is soluble in water. it's somewhat less irritating 
to lining of blood vessels. this would be better if you ahve to give it 
repeatedly in the same vessel. also, due to solubility differences, 
uptake of diazepam from IM injections is somewhat irregular. but, is it 
adequate? is it adequate enough? are there other considerations? what 
about cost? midazolam uptake is more efficient b/c of solubility. 


consider 50 kg violent dog. cost for diazepam would be about $2. cost of 
midazolam would be about $100. if you double the dose of diazepam to make 
up for inefficient uptake, that's $4. still not $100. 

zolezepam - 
duration in dogs/cats - in cats, much longer than in dogs. important when 
using telazol, because of effects of tiletamine in each spp. 

flumazenil 
- benzodiazepine antagonist. normally you don't need one. in humans, 
useful for treatment of suicidal overdoses of benzos.

butyrophenone 
tranqs: cardiovascular effects less profound. 
droperidol is used in 
animals in innovar vet
azaperone one used in pigs
cardiovascular effects 
of droperidol not severe 
azaperone decreases HR, CO - unless they get 
excited
when azaperone is given to pigs IM and they are left alone, it's 
ok. if you disturb them too soon, or give it iv, they get markedly 
excited. 
some guy remarked that he used azaperone in elephants - one of 
them got highly excited. 
droperidol in dog causes grouchiness. normal 
temperament not a factor. if you approach them they will not be friendly. 
they will snarl and growl. if you persist in bothering them, will 
probably bite. lasts a few hours. 

another effect in dobermans - takes 
on appearance of dog in back of car with head disjointed (?) - head just 
bobs up and down when dog isn't paying attention to anything. lasts about 
a week.

note that with innovar vet, you don't see behavioral changes 
until after the fentanyl wears off or is reversed. 

alpha2 agonists - 
tranquilizers in animals, to treat hypertension in humans. marked 
cardiovascular effects. use and utility discussed a lot.
clonidine - 
orally in humans for hypertension, xylazine - veterinary drug, detomidine 
- released for use in horses, medetomidine - use in dogs, dexmedetomidine 
is being investigated for use in humans,

alpha agonists:

alpha 1 - 
phenylephrine
alpha 1 and alpha 2 - epi and norepi
alpha 2 - clonidine, 
xylazine, detomidine, medetomidine

there are alpha2 receptors in various 
areas - some in periphery, many in CNS and cord. two main places to 
consider - one is postsynaptically in arterioles, two is presynaptically 
in CNS. so in normal sequence, peripheral effects: neuron is activated to 
release norepi, it goes and attaches to receptor, causes 
vasoconstriction. when alpha 2 agonist is administered, it will attach to 
the receptors and cause vasoconstriction. central effects -  when the 
agonist is given it will attach to presynaptic receptors, inhibiting 
release of norepi.

if you give something that causes vasoconstriction, 
what happens to BP and HR? BP goes up, HR goes down (vagal). when you 
give a drug IV, if it has peripheral and central effects, peripheral 
effects are likely to occur first because drug is in periphery first. so, 
first you see vasoconstriction, increasead BP, and bradycardia. then 
central effects occur - inhibiting norepi release in many areas of brain, 
causing decreased sympathetic outflow. if you decrease sympathetic 
activity, you see reduced HR, decreased force of contraction, decreased 
cardiac output - so bradycardia, decreased CO. if you decrease CO, and 
the periphery stays the same, BP drops. so you give an alpha 2 agonist. 
initially you see increased BP and bradycardia, then you see increased 
bradycardia, and some reduction of BP. because effect of the agonist on 
arterioles is direct, the vasoconstriction will stay in place. you're 
left with vasoconstriction, decreased HR, decreased CO. BP depends on 
intensity of vasoconstriction and intensity of decrease in CO. the 
decreased HR and CO always occur with these drugs, in all species. the BP 
is more variable. likely to go up initially, then go down to below normal 
over time. but it varies. 


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