----start---
pharm
1/30/98
klide

we're now on p 28

IV anesthetics, 
continued 
used to induce anesthesia:

thiopental - probably most 
commonly used anesthetic in veterinary medicine or was until recently. 
used in almost all species. it's a generalized depressant. people have 
tried correlating EEG with depth of anesthesia - that doesn't work. 

cardiovascular effects - typical of barbiturates. sensitizes myocardium 
to arrhythmogenic effects of catecholamines, decreases cerebral blood 
flow. we'll point out drugs that are useful in terms of cerebral blood 
flow b/c brain is in a rigid container, and if it swells it will get 
damaged due to pressure and impaired flow, so often we need drugs which 
do not raise intracranial pressure, or might lower it. drugs that 
decrease cerebral blood flow tend to lower intracranial pressure, so 
thiopental is useful then. also inhibits production of NO which might add 
some vasoconstriction and help prevent falls in BP when it's given. 


removal of thiopental from patients: talked about before, will repeat 
now. first point is, it is highly protein bound. importance of this is if 
the patient has lower than normal protein, there will be marked increase 
in free active drug, so if you give drug by weight and don't consider 
hypoproteinemia, you will markedly overdose it. liver, body fat, and 
redistribution - effects on thiopental: thiopental very fat soluble. 
blood flow to fat in ml/gr is low, but eventually thiopental gets to fat 
and is taken up by it. when one looks at duration of effect of a drug 
like an anesthetic, you choose a time to decide when recovery is. when 
animal lifts head, gets sternal, stands, or is normal. amount of fat 
probably influences lenght of time until animal is totally normal - 
increases is - esp in greyhounds. thiopental is metabolized by the liver, 
important with repeated doses. regarding redistribution - if you give it 
IV, first it is all in the blood, then blood level falls and the highly 
perfused viscera get a large amount of the drug. as time goes by, the 
drug is taken up by lean muscle, and then fat. as the uptake occurs in 
lean muscle and fat, the levels in blood and highly perfused viscera 
falls. early recovery from many IV drugs is due to initial redistribution 
(including thiopental).

where do greyhounds fit? they tend to be lean, 
have lots of muscle mass. but, pet greyhounds may be heavier. also, we 
often talk about anesthetics having special effects in sighthounds. the 
only work done in any breed of sighthounds was in greyhounds. there are 
no real papers showing any effects in any breed other than the greyhound. 
but, from clinical experience and body conformation, people include other 
breeds - whippets, italian greyhounds, ibizan hounds, pharoah dogs (see 
handout)

what happens in these dogs given a dose of thiopental, if you 
look at blood level over time, blood level is always higher in the 
greyhound than in a crossbred dog. this may be due to lack of fat and 
redistribution, but also a major reason is the liver of greyhounds 
handles it less efficiently so metabolic rate of thiopental breakdown is 
slower. so their recoveries are longer.

almost every breeder of every 
breed thinks that their breed is sensitive to anesthetics. there is 
little information out there - dr klide thinks breeders are relating 
experiences from the distant past, when veterinary anesthesia wasn't 
good, and lots of animals died or had prolonged recoveries. this has 
changed, but people remember.

calves also are a special circumstance - 
sleep much longer than adult cattle after thiopental administration, so 
they get reduced dose. shouldn't use at all in calves under 2 mos due to 
very prolonged recovery

undesirable effects:
anaphylaxis - very rare

prolonged recovery with repeated doses - common with repeated doses. 
first dose - 15 min recovery. 2nd dose - 20 min. 3rd - 30 min. 4th - 75 
min. as you give repeated doses, fat and lean tissue "fill up" and body 
relies on hepatic metabolism instead of redistribution for early 
recovery. so recovery is prolonged, because hepatic metabolism is 
relatively slow compared to redistribution.
effects of atropine on 
thiopental induced sleeping time: in clinical doses, when given with 
usual dose of thiopental, atropine will double the sleeping time. in our 
usual clinical use of thiopental (induction with a single small dose 
followed by a long period of inhalant anesthesia) this isn't usually 
important. but if you are anesthetizing a greyhound and premed with 
atropine, that would really prolong the recovery. also there are other 
anticholinergics - glycopyrrolate, which doesn't cross BBB or placenta, 
does not extend recovery time like atropine does. 

thiamylal: no longer 
available. don't discuss. was commonly used, but FDA didn't like the way 
it was mfrd, and company abandoned it instead of redoing it.


methohexital: an oxybarbiturate, very short acting. used in people and 
vet med. was used a lot in greyhounds, because recovery is shorter than 
from thiopental, but disadvantage is it causes more excitement during 
induction and recovery. sometimes you can prevent or treat this with 
sedatives, but the excitement from this drug is marked and hard to tx.


pentobarbital was used as anesthetic for many years, isn't any more 
except sometimes in lab animals

phenobarbital does produce anesthesia, 
but isn't used that way anymore. used to treat epilepsy

etomidate and 
propofol: these have become increasingly popular, used a great deal now.


etomidate: highly protein bound like thiopental, 76% in dogs. has an 
effect on GABA receptor, which is part of the site of action. also some 
evidence for effect on A2 receptors, but not sure what role they play. 
its major use is in animals that have cardiovascular dysfunction, due to 
heart disease or systemic disease or whatever. it is the most sparing of 
cardiovascular function of most of the IV and inhaled anesthetics. no 
changes in HR, BP or CO in normal dogs, very little change in sicker 
dogs. duration prolonged in greyhounds but still very short. short in all 
dogs. it inhibits production of corticosteroids. when originally released 
for use in humans, when there is need for prolonged sedation of patients 
in ICUs, they thought they could use this drug for it because recovery is 
short even with prolonged recovery. they didn't know about steroid 
impairment, but they saw increased morbidity and mortality in ICU 
patients who got prolonged doses. now they know it inhibits production of 
corticosteroids. pathway for production of corticosteroids and 
aldosterone involves two mitochondrial sites that this drug interferes 
with - desmolase, the cholesterol side chain cleavage enzyme, and 11 beta 
hydroxylase. so it interferes with those sites and prevents formation of 
cortisol and aldosterone for 4-6 hrs. this isn't a problem in most cases 
we use the drug for. if it were a problem, we could give replacement 
steroids but we don't usually have to do that. many drugs arne't very 
soluble in water, so to increase solubility so volume of injection is 
reasonable, they may use a different solvent - for etomidate they use 
propylene glycol. therefore, osmolarity is very high, so it can cause 
hemolysis. in most circumstances the dose is small enough that it isn't a 
problem. if you're concerned, you can dilute it with isotonic saline to 
decrease this effect. negative aspects of this drug - often produces 
myoclonus (muscle twitching) in single isolated muscle or lip. usually 
short lasting. incidence is decreased of you also use tranquilizers or 
opiates. it also causes vomiting, and the incidence similarly decreases 
with sedatives or opiates. drug is quite expensive, but for very sick 
patients who do not tolerate other anesthetics, this is very useful. 


propofol aka Rapinovet: this is quite commonly used in humans, fairly 
common in veterinary medicine. has interesting properties that are 
useful, and some that are problematic. this is a milky white liquid. it's 
a phenol derivative. because of that, you should consider it might be a 
problem in cats. we'll discuss that. it's not particularly soluble. the 
initial solvent used was something that caused histamine release, esp in 
dogs. in 1983, they changed from that to the current prep, which is an 
emulsion, which is mainly soybean oil, and some glycerol and egg 
lecithin. it's like IV tofu :). reason for mentioning this is if you look 
in literature, you have to know which preparation was used - if original 
prep was used in dogs, results will be very different. propofol 
potentiates GABA as almost all anesthetic appears to do. it's very short 
lasting. very very short lasting. even w/repeated doses recovery is still 
short. may be a bit prolonged compared to original recovery, but still 
very short. very rapidly metabolized in liver, but clearance is higher 
than hepatic blood flow, so it is also metabolized somewhere else - 
likely the lung. it's taken up by the lung. the majority of an initial 
dose is taken up by lung. the nonhepatic metabolic site hasn't been 
clearly defined. patients receiving liver transplants obviously lack a 
liver for a time while old one is gone and new one is being put in. 
people gave propofol during that time, then assayed for metabolites, and 
found them, so they are obviously produced somewhere aside from liver. 
recovery in sighthounds longer than in crossbreds but still short. very 
very highly protein bound. it depresses cardiovascular function - 
decreases HR, BP, CO, and systemic resistance. these decreases are due to 
direct negative ionotropic action and direct effect on arterial and 
venous tone. stimulates release oF NO which may be cause of vasodilation 
in arteries and veins. it is very useful for short procedures, even for 
longer ones b/c can be given by infusion and still have short recovery, 
or used for induction w/o lengthening recovery period. used a lot esp in 
sighthounds. concern: using it in patients w/brain dysfunction - ischemia 
and/or hypoxia in brain causes release of glutamate, causing 
neurotoxicity. thiopental decreases the glutamate mediated toxicity; 
propofol seems to enhance it. because of these differences there is 
concern about using propofol in patients that might have cerebral 
ischemia or hypoxia. no histamine release with current preparation. some 
pain on injection in humans; animals don't seem to show a problem. some 
excitement  - very small amount. less than with the other drugs we 
discussed. produces occasional twitching, short lasting, one body part. 
might be anti-emetic - seems so in humans. if you give repeated doses to 
cats, causes heinz body formation. appears to cause oxidative 
degeneration of cat Hb with repeated doses. sometimes there is prolonged 
recovery in cats. is used in cats, but you have to know about this. 
rabbits - light level of anesthesia resulted in death of 40% of rabbits 
in one study.
there is a response that occurs in humans that some 
patients waking up start to have dreams and actions relating to sex - not 
sure if it happens in animals. also produces a state people might enjoy, 
so there is concern about abuse of this drug. so this is a very useful 
drug with the concerns as noted.

steroids: there are several drugs that 
have steroid configuration that produce anesthesia. they usually don't 
get successfully marketed. one mixture was marketed for vet and human 
use. human product has been withdrawn, vet product still marketed in 
europe. the two drugs in it aren't very soluble - uses same propofol 
solvent, causes histamine release, so used only in cats and primates (see 
handout for name?). 

dissociative anesthetics: cyclohexylamines

cavalierly used in vet practice all the time in many species


phencyclidine - first one made. used as anesthetic in humans. high rate 
of psychosis, psychotic rxns. no longer used or made legally, but abused 
a lot. was sold as sernylan, sernyl, for use in NHPs, made handling them 
easier.

ketamine: released for use in humans and animals at about same 
time
tiletamine: started out at same time as ketamine, but not released 
for 20 yrs.

animals that these are used in - primarily cats and NHPs at 
first, then more in other animals. utility is different in other spp, esp 
with dogs. ketamine appears to separate patient from environment and is 
consistent restraint drug. once animal starts to look affected, animal 
isn't likely to exhibit any defenses. will ignore surroundings. there is 
an effect on the diffuse thalamoneocortical projecting system. is 
noncompetitive NMDA receptor antagonist.
can produce seizures. rare in 
domestic cats, common in nondomestic cats, common in dogs. increases 
cerebral blood flow and intracranial pressure - avoid in animals if 
you're concerned about that. it has in some spp a marked effect on 
skeletal muscle tone.

cat on ketamine:
eyes open, pupils dilated, tongue 
protruded, forelimbs rigid, hindlimbs also stiff. if you roll it over on 
its back, rigidity is enhanced. if you give a tranquilizer like diazepam, 
they get soft, relaxed. then when you roll them on their backs, they're 
floppy. so mixtures of ketamine and tranquilizers in cats are very 
useful. 

respiratory effects: depression. that is, the pCO2 will go up. 
the pattern of ventilation also changes - normally it's 
inhalation/exhalation, pause. animals given any of these drugs, their 
ventilatory pattern becomes apneustic. they inhale, pause (hold breath), 
rapidly exhale, inhale again, hold breath, lather rinse and repeat.


cardiovascular effects: in the dog - three different doses were given and 
effect over time looked at. arterial BP goes up with all three doses. 
more important, the biggest increase was produced by the smallest dose. 
larger doses produce smaller effects. why?
cardiac output is increased 
with all three doses, but biggest increase is from smallest dose. same 
thing with heart rate. why? how could that happen?

what are the ways 
drugs can affect cardiac function? can affect the baroreceptor pathway. 
but what are the parts making BP be what they are? CO, and peripheral 
resistance. so how hard the heart pumps affects pressure, and resistance 
affects it. drugs can affect either of those things directly, but the 
sympathetic NS also controls those things so drugs can have indirect 
effects via sympathetic NS. for an isolated heart/lung prep, if you give 
ketamine, you get dose related depression of HR, and CO. increasing doses 
make it fall. ketamine is a direct myocardial depressant - but it's a 
sympathetic stimulant. at higher doses, you increase sympathetic 
stimulation only up to a point, but myocardial depression gets greater 
and greater. so that's what we see going on here. 

increased salivation. 
vomiting very rare. these drugs do cross the placenta. excretion - marked 
differences b/w species. most spp metabolize it fairly rapidly in the 
liver. in the cat, it's excreted mainly unchanged, so duration of effect 
of these drugs in cats is longer than in other spp. 

clinical use: often 
used in domestic cats. alone causes severe rigidity which would interfere 
with positioning, but with phenothiazines, benzodiazepines, or A2 agonist 
tranquilizers, relaxation occurs. to anesthetize cats with only ketamine, 
dose is very high, which prolongs recovery. ketamine alone is not a good 
anesthetic for these reasons. when you add various tranquilizers, it's 
much better and dose is reduced, duration isn't so long, rigidity is 
reduced. there is some concern about using it w/A2 agonists. A2 agonists 
cause vasoconstriction, which increases afterload, and then the ketamine 
increases HR and CO. so there have been reports of arrhythmias and 
pulmonary edema w/ketamine in some spp. still, ketamine and A2 agonists 
is commonly used in cats and dogs. ketamine also used in horses after 
premed with A2 agonists. useful for induction but if you keep giving it 
there is marked excitement in recovery. nondomestic cats and other spp - 
useful with tranquilizer. many nondomestic cats will convulse with 
ketamine, but not if tranquilizer also used. the use of ketamine in dogs 
has become common. ketamine isn't approved for use in the dog, but that's 
ok - vets can use drugs for unapproved purposes if they can defend their 
use (in court). some drugs are easy to defend. diazepam isn't approved 
for use in any animal, but use is easy to defend - tons of literature 
about safety and efficacy. ketamine in dog as an anesthetic is harder to 
defend. many other safe, effective anesthetics labelled for dogs are out 
there. but many vets use ketamine in the dog. they rarely use it here, 
because of the cardiovascular effects (some people like the stimulation 
of myocardium), you sometimes see pulmonary edema and heart failure. 
recoveries are often bad, with lots of excitement and fever and 
vocalization. also subjectively, Dr. Klide thinks that "dogs don't like 
it." cats, when recovering, look abnormal but not distressed (except a 
small subset of cats that totally freak out), but dogs look upset. with a 
really bad, especially large dog which we can't restrain, we may use it 
because dr klide is more worried about humans safely handling it, and 
these drugs are most consistent for restraint.

---break---

so, ketamine 
by itself isn't useful in most spp because dose required is high, 
convulsions occur, stiffness occurs, recovery is long. mixing with 
tranquilizers lowers the dose, shortens the recovery and reduces 
convulsions.

PCP was the first one of these. systemic effects similar to 
ketamine, duration was longer in cats, seizures occured, stiffness 
occured in primates (but not as much as cats on ketamine. primates not 
stiff on ketamine). PCP only available illegally now. also called angel 
dust, or horse tranquilizer, although never used in horses. 

ketamine: 
effects in humans similar to those of PCP. increasingly abused by people. 
commonly abused. not being illegally made, it's being stolen. one of the 
ploys people have used to try to aquire the drug is to call up, say they 
work for another practice, and they need to borrow some ketamine. you 
should call someone back at their office if they say that. commonly 
referred to as special K.

teletamine - not available by itself, only as 
a mixture with zolazepam in telazol. lasts longer than ketamine, in most 
spp. affects some nondomestic cats - siberian tigers and others - in 
weird way. after you give it, cat appears to recover, and then the day 
after they become abnormal again. not sure why, maybe a metabolite is 
produced and it builds up and has an effect, or maybe it is excreted into 
bile into GI tract and then reabsorbed, not sure. happens in about 50% of 
nondomestic cats that it happens to. diazepam in small doses seems to 
prevent the effect. not sure why. 

ketamine is used by itself in NHPs 
for restraint.
CV and Resp effects on other spp depend on what it's mixed 
with. most importantly, with ketamine and xylazine BP increases markedly. 
primary resp effect is depression and increased pCO2 with all the 
mixtures.

regarding telazol - the ads imply that it is better than the 
other mixes because it is already mixed. but, that advantage is also the 
disadvantage - it's a fixed proportion. the duration of effect of the two 
parts are quite different. if animal starts to recover and you aren't 
done, you have to give another dose of it, and the effect of the longer 
lasting drug will increase more and more because it accumulates. you 
can't just give the one that's wearing off. you could give another drug, 
but then why bother with the mix in the first place. the only real 
advantage is that it comes as a powder to reconstitute, and when you're 
using it in a projectile dart eg with exotics in zoo, or wild, or for 
animal control, that's useful - the volume of drug is important because 
the darts are small. think of the tiger. dose of telazol would be 3 mL. 
with ketamine it would be much larger. you could freeze dry the ketamine 
and then reconstitute it at double the concentration to half the volume. 


also re: drug mixtures - one of the uses of medetomidine with ketamine is 
that it allows the dose of ketamine to be markedly decreased, more so 
than with xylazine. so when you're using ketamine, and you want the 
recovery to be short, this is useful. if you give A2 agonist with 
ketamine and then reverse the A2 agonist, you're left with ketamine's 
effects alone, which aren't good. with medetomidine, you can use much 
much less ketamine, so less of a problem after you reverse the 
medetomidine.

Guaifenisin?: muscle relaxant, some sedation, cough 
suppressant.used for induction of anesthesia with thiopental in horses. 
only for coughs in people. 
horses given thiopental will respond 
vigorously - get excited, may refuse to move, etc. if you add 
guaifenisin, it slows horse down, makes it easier to move it around,makes 
it more controllable. it has some effects on BP (decreases) but not too 
much to deal with. not used in small animals.
need to make very dilute 
solution, so you have to give a lot, but otherwise it causes hemolysis. a 
lot of hemolysis.

there are three ancient drugs, last of injectables on 
our list:

chlorolose: was used, but use is markedly diminished, for 
physiologic or pharmacologic studies, because it didn't enhance reflexes 
- may have enhanced them. but it isn't a good anesthetic. causes 
convulsions, doesn't produce much analgesia. historically, was used with 
NMBA so paralysis covered things up, but that is unpleasant for animals. 
IACUCs will disallow chloralose as an anesthetic unless it's for a 
pain-free procedure

urethane: rarely used. carcinogenic for people using 
it. so people don't want to use it.

chloral hydrate: used a long time 
ago as anesthetic and sedative. worked, but inductions weren't good, 
recoveries were long with lots of excitement. used as sleep aid in people 
and as knockout drops to shanghai sailors. 

Inhaled anesthetics: first 
ones were used in middle of 1800s. there are many chemical structures 
that produce inhaled anesthetics. most of the inhaled anesthetics are 
liquids at room temperature. partial pressure = pressure exerted by 
component of a mixture -> atmospheric pressure is made of partial 
pressures of oxygen, nitrogen, CO2, etc etc. the amount of each of those 
things produces the partial pressure for that substance.


multiply 
concentration x total pressure to get partial pressure of a substance.


when evaporation occurs, molecules escape from surface of liquid. with 
boiling, also from down in the liquid. vapor pressure is partial pressure 
of a vapor in equilibrium with a liquid. if you have a container of glass 
with halothane in it, the liquid will start to evaparate. molecules will 
leave surface. if container is closed, molecules entering air will 
increase,accumulate in air, and finally some will go back into liquid- 
equilibrium is reached when amount leaving liquid equals amount returning 
to liquid. the partial pressure of the liquid at equilibrium is the vapor 
pressure. the concentration of molecules in air above the liquid is the 
saturation concentration. the vapor pressure of liquids changes with 
temperature. as temp goes up, vapor pressure goes up.
vapor pressure and 
saturation concentratoin are important, also that they're affected by 
temp. on p 38 are some numbers - blood gas coefficients of anesthetics, 
vapor pressures. 

numbers to remember: 

MAC and blood gas coefficient, 
and vapor pressure at rm temp for some of these anesthetics

SEE HANDOUT 
for all this vapor stuff. i'm not sure i'm getting it all.

blood gas 
coefficient - ratio of concentration of stuff in blood compared to 
concentration of stuff in gas above it. similar to oil:gas coefficient. 
for halothane, 2.3, isoflurane, 1.4

we'll repeat over and over but won't 
believe and will forget this:

there is a relationship b/w blood gas 
solubility coefficient and speed of induction and recovery. the less 
soluble the anesthetic, the faster induction and recovery.

MAC we 
discussed before.

the basic effects of inhaled anesthetics: CNS 
depression in general, most of them. some will produce EEG patterns that 
are similar to seizures - same as seizures. enflurane most likely to do 
that. it will produce spikes on EEG same as spikes produced by seizures. 
depending on species you may actually see a convulsion. one of the 
problems with enflurane use in our environment, where students do 
anesthesia, in general one interprets movement in the patient as being 
too lightly anesthetized - but with this drug, could be twitching in 
response to drug and be already heavily anesthetized. all are respiratory 
depressants, dose related. cardiovascular effects - all produce decreases 
in BP, CO, and most often decreases in HR. there are some differences b/w 
them. some people make more of a production about this than others. in 
general, the CO will be depressed less by isoflurane than halothane at 
equivalent doses. in general, iso will cause more vasodilation than 
halothane. the effects on cerebral blood flow: all increase cerebral 
blood flow. some people argue about the amounts, but they all do do it to 
a significant amount. clinical difference b/w the agents - if you're 
concerned about intracranial pressure, one way to decrease cerebral blood 
flow is to hyperventilate the patient since it's controlled by CO2 level. 
if you blow off CO2, can decrease cerebral blood flow. if you 
hyperventilate while giving one of these drugs, cerebral blood flow will 
be in between. with iso, can easily overcome increase in flow via 
hyperventilation, but with halothane it isn't so easy. effects in liver 
and kidney we'll get back to. all the potent volatile liquid anesthetics 
are metabolized but to very different degrees. anesthetics may cause 
mutation, cancer, and fetal abnormalities. there is a major concern about 
chronic exposure of peopel to low levels of inhaled anesthetics, because 
it may cause some things - clearly causes increased irritability, 
headaches. may cause increased incidence of cancer or spontaneous 
abortion in pregnant women - not clearly defined. there was evidence 
showing it did, evidence showing it didn't, so equipment was put on the 
machines to prevent gases from leaking into rooms, so point is moot. with 
appropriate scavenging, levels approach zero. 
onset and recovery vary 
with solubility. 
duration is as long as you give the drug. amounts 
depend on the drug. 1 MAC prevents movement in half the individuals 
getting painful stimulus. 1.3 MAC is surgical anesthesia. inhalents are 
all respiratory depressants and produce apnea at high doses. all can 
produce hypotension and cardiac arrest at high doses. all cross placenta 
and will affect fetuses. 
increase in spontaneous abortion - mostly 
studied in pregnant women working in ORs, but also there was an increased 
incidence in women who were bred by men who were working in the OR. 


diethyl ether - one of first anesthetics, used a long time, still a bit 
in labs. ether explodes if you put it in the refrigerator. why? it has a 
very high vapor pressure. if you cool it, you decrease vapor pressure, 
slowing [note: check this. he said slowing, I'm not sure if he meant 
slowing] rate of evaporation. this is the same reason you don't put 
bananas in the fridge [well, bananas don't explode but they overripen]. 
when you open the fridge the compressor sparks and it can blow up if you 
had ether in there. some rabbits euthanized with ether were put into a 
fridge once and it blew up. two reasons to use ether: one, as an 
anesthetic in small lab animals (rats, mice) - was used by inhalation 
w/no vaporizer, because concentration made when it evaporated was a 
reasonable concentration for inducing anesthesia. can't use iso and 
halothane that way, but methoxyflurane can be. the other reason people 
say they need ether is to remove adhesive tape or put it on. if you pour 
it on the adhesive tape, it gets sticker and sticks on better, then 
evaporates. then, when you get it off, you can pour it on again, and it 
helps you get it off. but,now there are other nonexplosive solvents for 
that. no reason to have ether at all. 

halothane: very commonly used. 
was used a lot in humans before isoflurane. vapor pressure and MAC are in 
handout. not stable, so mixed with thimalt (?) which has implications for 
vaporizer. is general depressant, decreases HR, pressures, CO. has more 
of an effect on heart and less effect on periphery. sensitizes myocardium 
to arrhythmogenic effects of catecholamines. respiratory depressant, pCO2 
increases. very potent, useful bronchodilator. animals with 
bronchospastic disease do well with it. 20% of inhaled halothane is 
metabolized. it was noticed in humans that some cases of hepatic failure 
occured unexpectedly in relatively healthy young patients undergoing 
elective procedures. this liver toxicity appeared in those people. there 
was an attempt made to determine if this occured more frequently with 
halothane than with other drugs used then (in the 60s). almost a million 
cases were studied and they couldn't figure it out. so many things happen 
to people in hospitals that can cause hepatitis - infections from 
caregivers, blood products, whatever -  that they couldn't figure it out. 
information in animals still less clear. there is only documented 
hepatitis in some strains of colored guinea pigs - some of them get 
hepatitis after getting halothane. the only way to recreate the syndrome 
in other spp was to give prolonged doses of phenobarb, and then create 
hypoxia while anesthetized with halothane. so people worry about 
halothane in animals with liver dz but there is no evidence that it is a 
problem. blood gas solubility coefficient = 2.3, relatively insoluble - 
induction and recovery fairly quick.

methoxyflurane: metofane. used in 
lab animals. common in vet med before iso. use markedly decreased. 
decreases resp and cardiovascular function as discussed. half or more of 
it is metabolized - most of any of these. one of the metabolites is 
inorganic fluoride. shortly after its release for use in humans, there 
was an increase in unexpected renal failure. then, in the 60s, it wasn't 
known that these drugs were metabolized. so tehy figured it out. the 
fluoride was nephrotoxic. see handout for info on nephrotoxicity. if one 
gives almost any species methoxyflurane in reasonable amounts - gave 1.5 
mac to dogs for 3 hrs. measured inorganic fluoride levels in blood. level 
rapidly rises once you start giving the drug, peaks at 3 hrs, then slowly 
falls over 7 days, back to control levels. the peak was about 200 mmol/L. 
in humans, threshold for nephrotoxicity is 20-50/L and 200 is lethal. so 
if 10 people were anesthetized in this way they would have all died of 
renal failure. the reason this iddn't happen, is in general humans get 
reduced amounts of multiple agents, so they didn't produce this much 
fluoride. in doing the studies, people had difficulty creating this in 
animals. threshold in dog for renal dysfunction is 200 mmol/L and lethal 
is 400.that's why. it's harder to reach lethal dose.
there are times when 
fluoride level would be higher - if concentration given was over 1.5 MAC 
- with methoxyflurane, changes in signs of depth of anesthesia are more 
subtle, so it's easy to give more than an animal needs -this raises 
fluoride level. also if procedure lasts longer, or if patient is obese 
(it's very fat soluble) more is produced. if patient is on drugs that 
stimulate microsomal enzymes, like phenobarbs, they are more efficient 
metabolizers. an old, fat dog with a pyometra and renal dysfunction, 
that's an epileptic on phenobarb, should not get methoxyflurane. there's 
one strain of rat that responds at the same levels as humans - Fisher 
something rat. gets renal failure at same level as humans. blood: gas 
solubility coefficient is about 12 or 13. that makes it a slower 
induction/recovery than halothane. it's the slowest of all. it's very 
soluble, lots is taken up, so induction and recovery are prolonged. 

---end----