----start----- pharm 1/26/98 Dr Klide exam - a week from today. 2 hrs. 68 questions. except for robinson they're short answer/fill ins. Robinson's will be similar to his review. For the next 8 hrs, we'll discuss the perianesthetic period - also many drugs. many of the drugs we have some understanding about their mechanisms, some we don't. we do understand pharmacodynamic effects. we won't have to know drug structures, but we do have to know differences b/w them eg if they have structural differences that cause them to be metabolized differently. drugs with common properties are grouped together but still have many differences. perianesthetic period - starts with preanesthetics - drugs given immediately/1 hr before anesthesia. There may be anticholinergics, analgesics, tranquilizers, or sedatives given. animals are still awake during this period. induction of anesthesia is transition from waking to sleeping state. maintenance of anesthesia is just that - uses injectable or inhaled drugs. postanesthetic period is the time in which animal recovers and goes from being asleep to awake. during recovery most common things to treat are pain caused by the surgery, or excitement from the recovery from the drugs. definitions: tranquilizer: ideal is to have an effect on some abnormality without affecting normal function. this is how you hope to use it in humans and behavioral medicine. in anesthetic period, using drugs in that manner, in doses that would have minimal side effects, the restraint would be inadequate, so we use higher doses and get more side effects. If you had a junkyard dog that you can't handle, you'd have to heavily tranquilize/sedate it to make it able to be handled. The tranquilizers are divided into major and minor tranquilizers. Major: in humans, to treat psychosis - drugs are not addicting, may cause extrapyramidal signs which are abnormal motor movements. common example - chlorpromazine or acepromazine. Minor: in humans, treat neurosis, don't cause extrapyramidal signs, are addictive. in general, these tranquilizers aren't adequate for chemical restraint by themselves. eg diazepam. Sedatives: there are some drugs that produce different degrees of effects depending on dosages. sedative, hypnotic, anesthetics. sedatives cause decreased motor activity, cns depression, and could lead to sleep - eg pentobarb. then if you increase dose, may produce Hypnotics: cause sleep, potentially anesthetic - drugs like this are used to help people fall asleep - eg pentobarbital at higher dose further dose increase - individual becomes anesthetized. further dose increase - death from cardiovascular and respiratory failure. Opioids (narcotics - this word used to be used for opioids, but now the gov't has taken over that word. opiates - drugs with structures similar to morphine): opioids have properties similar to morphine, have effects at opiate receptors. neuroleptanalgesics - drug mixtures, usually tranq and opioid, that have more profound effects than either drug alone. eg morphine and promazine, or fentanyl and droperidol. opioid antagnonists: drugs that attach to same receptors as opioids and displace them, but have no effects. reverse effects of opioids. opioid agonist/antagonist analgesics: these drugs are agonists at some opiate receptors, and antagonists at other opiate receptors - generally are used to produce analgesia. amnesic: drugs which produce memory loss. if you give them on purpose hopefully the loss is temporary. you use them in human medicine for people undergoing unpleasant procedures while awake, so they don't remember it. hallucinogen: produces hallucination eg perception w/o stimulation, eg LSD. some drugs are pure hallucinogens, some cause them as a side effect. classical anesthetics produce analgesia, sleep, muscle relaxation, and decreased reflex response to pain - eg diethyl ether nonclassical anesthetics eg ketamine - don't produce all four classical signs of anesthesia dissociative anesthetics - cauase mental detachment eg ketamine local anesthetics - produce anesthesia/analgesia locally by affecting nerves/nerve endings. eg lidocaine. Local anesthetics: slide of painting showing the use of zombies. slide of a puffer fish. slide of some frogs which elaborate arrow poison. slide of coca cola label. slide of cocaine. what do these things have in common? they are all related to substances that interfere with sodium channels. desirable properties: need to be injectable, block sensory fibers, be effective in small amounts, need to be able to put them near specific nerves, be non irritating, excreted relatively quickly, low systemic toxicity, duration of action must be appropriate to desired event. most commercially available local anesthetics meet these needs. can be divided into two groups, by structure: if there is a COO ester linkage or if there is an HNC amide linkage between the two main residues. Amide local anesthetics are broken down by enzymes in the liver. Ester locals are broken down by circulating pseudocholinesterases - procaine and tetracaine are esters and are older drugs. Procaine not used much at all. Lidocaine and bupivicaine are amides. Procaine was the first commercial synthetic local anesthetic. first local anesthetic was cocaine but that wasn't synthetic. Procaine trade name was novocaine. Many dentists giving a local will claim to be giving novocaine but in fact they are probably using lidocaine or mepivicaine. it's important to be clear, though; some people are allergic to some local anesthetics. with a few rare exceptions, people allergic to locals are allergic to the esters - eg procaine. only a few isolated people are allergic to amide locals. Lidocaine - most commonly used local in humans and animals bupivicaine also used - newer drug, most long lasting local. Cocaine is rarely medically used anymore. it could be used as a local - it was used in some procedures that are very bloody and require locals eg nasal surgery - cocaine causes vasoconstriction, so was very useful in decreasing bleeding. but, because of the high incidence of abuse and theft, most people use other drug mixtures that cause similar effects without the high. benzyl alchohol - common preservative in many injected drugs that come in containers meant to be used repeatedly - multidose vials. it also has local anesthetic properties. cetacaine - mixture of two local anesthetics. one of the other differences b/w cocaine and other locals is cocaine inhibits reuptake of many NTs, probably accounting for the high it produces. inhibits dopamine, serotonin, and norepi reuptake. mechanisms of action: different ways to block nerve conduction - only a few are common. there's a receptor on external membrane surface at sodium channel, and on internal surface for sodium channel. some drugs like tetrodotoxin block the external receptor. clinically used local anesthetics block the internal receptor. effects of tetrodotoxin are important when studying it or eating puffer fish. it seems that substances or animal sources of this toxin are used to make zombies. the goal in eating puffer fish is to take in just enough toxin to make your lips and fingers tingle, and not die. some thickenings of external membrane/expansion of membrane - benzocaine. nerves have varying susceptibility to local anesthetics. two myelinated nerves with nodes - the narrower nerve will have more nodes blocked by the same amt of drug than a thicker nerve. smaller diameter nerves are more easily blocked, and blocked by lower concentrations, than the larger diameter fibers. this differential sensitivity to blockade is clinically important. in a horse, where local anesthetic is placed in epidural space in caudal cord to block pain for surgery eg to repair recto-vaginal fistula - horses give birth with great vigor, often causing these fistulas. if you give a high enough concentration of local and a large enough amount - fibers are blocked in order of decreasing size. smallest fibers are sympathetic fibers, middle are sensory, and largest are motor. so get back to the horse - you want to block the sensory fibers without blocking motor fibers - you don't want the horse to become recumbent and agitated. sometimes things are added to local anesthetics epinephrine most common thing to add. two reasons - it causes local vasoconstriction, impairs blood flow to area which does two things - slows removal of drug from area increasing length of anesthesia, and reducing the blood level of the drug, diminishing likelihood of toxicity. when locals are absorbed systemically, may cause many effects. in order of small to large dose effects: restlessness, apprehension with mild overdoses vomiting with increasing dose blood pressure effects (vary markedly b/w drugs) - drops in BP severe cardiac arrhythmias - most commonly w/bupivicaine high doses - seizures cocaine causes cerebral stimulation lidocaine - depending on dose, may see CNS stimulation or depression - quadriphasic effect on brain - high dose -> seizure; higher dose respiratory depression, apnea almost all these drugs we discuss are respiratory depressants - this means that arterial pCO2 will rise. it could be because TV has dropped, RR has dropped, or both. but definition of respiratory depression is that pCO2 goes up. at higher doses, severe cardiovascular depression of myocardium and peripheral arterioles; death. marked differences in uses of some locals Lidocaine: quite safe local. the toxic doses are considerably higher than the required doses for local anesthesia. if you look at effects of lidocaine - essentially no effect on BP and no change in EKG at high doses. lidocaine is often used to treat ventricular arrhythmias esp ventricular tachycardia. Bupivicaine: very different. electrical silence separated by seizures - EEG readout. at close to clinical doses, it will lower BP. often produces severe ventricular arrhythmias. can cause seizures. can't use this to treat ventricular arrhythmias! where do you put local anesthetics? infiltration: one method of placement is infiltration into local tissues. if a patient has a laceration you want to suture, you can inject along edges of laceration, blocking pain receptors and beginning of pain conducting fibers. topical: many parts of the body are covered with mucous membranes - can apply locals to that surface to produce anesthesia - so if there's a foreign body in the conjunctival sac, can put local in there to produce surface anesthesia. regional: specific nerve blocks for diagnosis of lameness in horses, for example. if horse is lame and you block nerves innervating different parts of leg, you can localize the source of pain. spinal and epidural analgesia: the membranes you hit when you inject -> first dura, then arachnoid, then pia. dura is thick, arachnoid is attached to dura, then you have CSF in the subarachnoid space, and the pia is attached to the cord. if you inject something into the subarachnoid space, so it mixes with CSF, that is a spinal. it may be local anesthetic, or you might inject dye or something. so injection into there is a spinal. injection between the vertebrae and the dura - the epidural space - is an epidural injection, and is used for procedures in caudal half of the body. in dogs/cats epidurals are used more often than spinals because they are easier. in humans, spinals were more commonly performed than epidurals in the past - in past 20 yrs, this has changed. epidural has enough advantages that people are using them more. in dog, cord ends at around L7, subarachnoid space extends a bit past. lumbosacral space is a relatively large hole; other spaces are a lot smaller. without fluoroscopy it's harder to get through other spaces. lumbosacral space in dog is easy to find and get through - subarachnoid space usually ends in front of it, so epidural is easy. in humans, cord ends at end of thorax, but subarachnoid goes all the way down, and space between vertebrae is large, so it's hard to stop before you enter subarachnoid space - so spinal is easier. if deciding b/w epidural or spinal, you have to know dose differences which vary b/w species. human is one extreme, sheep is another. in sheep, you use same dose to produce same effects with subarachnoid or epidural injection. in humans, 2 mL in subarachnoid space will produce abdominal analgesia, but to do same thing with epidural injection will take 20 mL. the difference in dose presents a potential toxicity problem. if you draw up enough drug for an epidural, and are mistakenly in subarachnoid space and you give all the drug, what happens? level of blockade depends on dose. if you inject more than you should, blockade extends too far cranially. you could block respiratory innervation, cause respiratory arrest. you could block intercostal nerves and phrenic nerve (midcervical). innervation to arterioles that controls systemic resistance - sympathetic innervation - this could be blocked too, causing drops in BP due to loss of vasoconstriction. intravenous local: procaine was used that way. lidocaine is sometimes used this way - fairly commonly. you can intubate animals this way. some spp have reactive larynx - dog doesn't, cat does. you have to diminish reactivity to intubate. could spray local onto larynx, or could give IV. so you use it during induction, IV. also gives some systemic analgesia this way. interpleural analgesia - animals that had thoracotamies can get pain relief this way. also into joints - diagnostically or postoperatively ----break---- procaine - shortest 30 min buvicaine - longest 3-6 hrs lidocain/mepivicaine middle - 1-2 hrs toxicity - allergies: not seen in animals, in humans more common w/esters FYI, people who have allergic rxn during dentistry are more often allergic to epi in the anesthetic, not the anesthetic. vomiting, hypotension, arrhythmias, seizures, death = other toxic effects. Birds are exquisitely sensitive to procaine is the party line, but Dr Klide says it isn't true. It's easier to overdose something that's small, that's the thing. If toxic dose in 20 gr bird (fat canary, skinny parakeet) is 1 mL, that doesn't take long to inject. to give the equivalent amount of drug to a 400 kg horse would take a lot longer - would be 20,000 mL. if it took 5 seconds to fill the syringe, it would take 2000 10 mL syringefulls to give, so would take 2.8 hrs to give it. in larger animals, dose for toxicity is smaller per unit weight, but if it were the same, it would take a long time to give. so this was the problem in birds. it's hard to measure tiny doses, and people often didn't think about the concentration required to block nerves - the fiber diameter is much smaller in the bird. so, if you use an appropriate dose, it shouldn't be toxic to birds. specific toxicities: tetracaine and benzocaine. if you look at doses of drugs needed to kill 1/2 the animals (LD 50) and take the IV dose vs intratracheal dose - for tetracaine, LD50 is same given IV or intratracheal. tetracaine crosses membranes really fast, then. for lidocaine, intratracheal LD50 is 5x IV LD50. so lidocaine isn't able to cross membranes as fast. cetacaine is a mix of benzocaine and tetracaine. benzocaine affects Fe++ changing it to Fe+++ which causes Hb to not carry as much O2 -> creates methemoglobin which results in hypoxia (potentially). so Cetacaine has two toxic drugs in it. the spray form of Cetacaine, therefore, can be dangerous. concentrations are high - it's made for adult humans. amt that comes out with one spray is high. a common method of desensitizing cat larynx is spray with a local anesthetic. but, Cetacaine is very unsafe, even though it's convenient. amount that comes out is large relative to size of cat. concentrations of drugs are high. can cause cardiac dysfunction or death from tetracaine; methemoglobinemia from benzocaine. so they don't use Cetacaine here. drug reactions/interactions: sometimes interactions are useful, sometimes bad. antihistamines - histamine has H1 and H2 receptors. H1: allergies; H2: gastric acid production. H2 blockers often given to people with ulcers. Now, lidocaine is given IV to tx arrhythmia, right? when you give it at a certain dose, it produces a particular blood level. If you give an H1 antagonist (benadryl) with it, nothing happens to blood level of lidocaine. if you give an H2 blocker, cimetidine, you get a very high blood level of lidocaine. why? not sure. two possible reasons - maybe: hepatic blood flow is controlled by H2 receptors, so if you give H2 antagonist, flow to liver is reduced, less rapid metabolism of lidocaine. maybe: cimetidine affects the enzyme that breaks down the lidocaine - competes with lidocaine for enzyme, or something. Opioids: drugs with properties like morphine that are reversible by opioid receptor antagonists. receptors: mu (main one), kappa (next commonly discussed), delta, epsilon, sigma. sigma was thought to be opioid receptor; now isn't thought to be specific to opioids, but might be in books still. effects of sigma agonists - fear, apprehension, dysphoria, hallucinations. phencyclidine, the dissociative anesthetic, stimulates this receptor also. mu - there is a mu1 and mu2 - mu1 are receptors that produce supraspinal analgesia (in brain), mu2 are in cord. effects of mu agonist - supraspinal analgesia and resp depression. kappa1- cord, kappa3- brain, kappa2 - not sure. agonists cause spinal and supraspinal analgesia morphine - agonist at mu and kappa naloxone - pure opioid antagonist at mu, kappa, delta pentazocine - mixed agonist/antagonist analgesic - antagonist at mu, agonist at kappa. slide: pretty poppy field. these drugs have been known for thousands of years. as poppy matures, it produces a seed capsule. local natives go out and make incisions in seed capsules, which allows milky material to drip out. this is then collected and it turns brown. the brown goo is opium. it contains many alkaloids, including morphine and codeine. some opioids are made by plants, obviously - these are called "naturally occuring" opioids. some drugs start that way and then get chemically modified - those are called semisynthetics. also, some are just synthetic. slide: structure of morphine. there are many substitutions that produce opioids with somewhat different characteristics wrt lipid solubility, vomiting, duration of action. remember that when the chain on the single N is changed, it often converts the substance from agonist to antagonist. antagonists are made by adding longer groups where the methyl group is. mechanism of action: multiple sites - slide of dorsal horn of cord - shows incoming nerves - alpha-delta and C fibers (fast and slow pain, temp, touch). recall lamina of rexed. multiple events occur in different layers. important points to remember are that the sensory/pain info comes in to dorsal horn, there are synapses at different levels, and other neurons impinge on those synapses and can affect transmission of pain info. we'll look at two primary ones. descending anti-nociceptive tract: goes down cord from brain, has neurons at all levels that enter dorsal horn and slow transmission of pain information. this descending pathway can be activated by giving systemic opioids, by using acupuncture. presynaptic inhibition - some of these neurons cause inhibition of release of substance P using enkephalin as an NT, but there are several systems involved. 3 systems involve enkephalin, serotonin, and something else - and these can inhibit transmisison of pain information. effect of opioids on different species: produce some excitement and some depression in all spp, but to varying degrees. humans: analgesia, some sedation, occasional excitement (less common) horses: tend to become excited - study shows them picking their feet up more often or something. increasing doses increase excitement. generally, over time, small doses increase eating behavior (like other illicit drugs), and as drug goes up, locomotor activity increases, finally getting uncoordinated. so, opioids are used to try to make horses run faster, sometimes. people who try to cheat in horse racing are good clinical pharmacologists. also are used in combination with tranquilizers for standing restraint. frogs: depression and excitement -first depression, then later the excitement occurs. mice: straub tail - s shaped tail carriage rats: get catatonic - stay in one spot. rabbit: depression with small doses, exaggerated reflexes with higher doses dogs: like humans, some excitement may occur. cats: analgesia, morphomania - high doses cause marked excitement. likelihood depends on dose, drug, and drug interactions. we do use opioids in cats. farm animals - most get excitement NHPs - depression other effects also vary by spp, but can categorize by comparing to behavioral effects. eg in dogs, opioids produce bradycardia of vagal origin. can prevent with anticholinergics. this occurs in all the spp that get depressed with opioids. animals that get excited by opioids get tachycardia. peripheral cardiovascular effects vary - smooth muscle relaxation is a direct effect, but may also cause histamine release, and histamine is a peripheral vasodilator. so if it causes histamine release, will cause more vasodilation that it otherwise would have. animals that are made quiet by opioids get bradycardia, animals that get excited get tachycardia, but BP effects vary b/w opiates in all species - will go over this. eg, in horse, one drug increases BP and HR, while meperidine causes marked drop in BP in horse. another consideration wrt vascular tone is cerebral blood flow - we'll talk about this too, in relation to the other drugs we use, and patients with raised intracranial pressure. what controls cerebral blood flow? does it ever change? does it change with BP? no, it doesn't change with BP. it changes with CO2 - increased CO2 increases cerebral blood flow. so if you have given drug that causes respiratory depression, it will increase cerebral blood flow. using opioids without controlling ventilation can raise intracranial BP. opioids change response to CO2 - it used to be said that opioids shift CO2 response curve to right and anesthetics change the slope, but that's not clear - the point is, respiratory depressants change the response to CO2, either making it less sensitive, or changing the slope. extreme depressants make the response zero. opioids cause salivation in dogs, and vomiting in animals that can vomit - stimulation of CTZ and emetic center. morphine stimulation of CTZ is blocked/reversed by opioid antagonists. another drug, a modified morphine - apomorphine - is often used to produce vomiting in dogs - via a dopamine effect. another important difference in opioids causing vomiting is that it's common when they are given SQ or IM, but not IV. this is not clear - but it is likely that the opioids are depressing the emetic center - so if you give it, it activates the CTZ which stimulates emetic center and causes vomiting, but if you give it really really fast, it depresses the emetic center right away. most of the GI tract is stimulated by opioids - muscle tone is increased; but propulsion stops. so you see initial defecation, then constipation. opioids cause contraction of gall bladder but also of sphincter of oddi - so pressure in gall bladder goes up. this can be of clinical concern. urinary effects - not clear. if you look at dog studies, there is a group where animals are awake/stressed, another where they are anesthetized. one response to stress is release of ADH, so this study on ADH isn't that great. opioids may decrease urine production via ADH. metabolism: liver, urinary excretion, lung. eye: effects on pupil vary - quiet species get constriction, excited species get dilation. uses of opioids: analgesics, sedatives, chemical restraint esp when mixed with other drugs, part of anesthetic technique, inhibit coughing (anti-tussive), treat diarrhea. they decrease MAC (minimum alveolar concentration, p 38). morphine produces a maximum MAC reduction of about 80% - it markedly reduces amount of inhaled anesthetic required for good analgesia. butorphanol (mixed agonist antagonist) produces only about 10% MAC reduction, for example. [MAC is used to compare anesthetic agents. it's the alveolar concentration of inhaled anesthetic at which 50% of a group of anesthetized animals will not respond to painful stimuli. so you can anesthetize to 1MAC, 2MAC, 3MAC, or whatever - and can compare different drugs. studying analgesics is hard in people, harder in animals. one way to determine if substance is analgesic is in anesthetized animal. if you anesthetize animal with inhaled anesthetic, and determine MAC, you can then do a study where you give a test drug, and reanesthetize, and redetermine MAC - and if your test drug was a good analgesic, MAC would be lower/smaller.] opioids are also being put into more areas to produce analgesia - eg epidural space. there are opiate receptors in the cord that will produce analgesia. the thinking is if you use it close to site of action, you can use less of it, and reduce the side effects. so over last 10 yrs, this has gotten more popular. people are also trying to use it in joints and stuff, and results are less clear. undesirable effects: remember, some opiates cause mast cells to release histamine. this is a direct chemical effect, not a receptor mediated effect. morphine and meperidine are very likely to cause histamine release. mixed agonist/antagonist butorphanol doesn't cause histamine release. oxymorphone, fentanyl also don't cause histamine release. there are clinical circumstances where histamine release is a problem - dogs with mast cell tumors have a lot of histamine, if it's released, they have big problems. so you'd have to choose a drug that didn't cause histamine release for this kind of patient. addiction - clearly a big problem in humans. also could be problem in animals, but patients do not have access and hopefully we don't create addicts. vomiting - often occurs defecation constipation - often undesirable unless txing diarrhea. excitement - usually undesirable except in racehorses. ----end-----