Pharm

2/4/02

Barry Hillam

Opiods – beginning with second lecture

Note: the first part of these notes are done carefully, with appropriate Lippincott quotes inserted. After that, they regress to what they were in the first place – just a rough rendering of everything I could get from what Gebhart was saying, with all typos and grammatical errors in their original splendor.

opiods -- euphoria; dysphoria is the opposite. Morphine also includes drowsiness/sedation. Not that they are barbiturates, but they do cause drowsiness.

People being treated for cancer -- opiods given in large doses. drowsiness is a problem with these people. This causes social problems with older people on a lot of morphine. This can also render them legally unable to sign a legal document like a will.

A couple strategies to minimize this drowsiness:

1. co-administer opiod with an amphetamine (work at alpha 2 adrenergic receptors). This leads to a greater than anticipated analgesia. So in this case you can actually reduce the opiod a little bit. PLUS the amphetamine stimulates CNS for a little more alertness.

2. Restrict area to which opiod is given. So with cancer patients, can give morphine in to epidural space. Here you get potent analgesia that is targeted to a specific area, reducing systemic absorption. So those are two strategies that can be employed.

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Some of the zany things that Opiods do:

Respiratory depression -- a way that opiod overdose can kill. This is not the way people die of a heroin O.D; heroin won't be totally pure. Autopsies of these people often show a massive pulmonary edema which is characistic of an anaphylactic response. Their first dose may have created sensitization to the heroin contaminants, so that they were sensitized. Then the next time they take it, OUCH. They die of anaphylactic shock. But back to respiratory depression; the amount of PCO2 isn't read properly by the brain, and deadly hypoxia is the result

Antitussive (anti-cough). (note that codeine, or dextromythorphan is in most cough medicines). Antitussive effects happen at relatively low doses. [normal analgesic dose of codeine is 30-40 miligrams]. [opiophobia -- people try not to sell codeine, so they recommend dextromythorphan instead, saying it is just as good as codeine. Well, it isn't just as good as codeine. But from the seller's point of view, it keeps the DEA away. Pharmacies want to lay off the codeine as much as possible, even though it may have more theraputic value]. "Codeine has greater antitussive effect than morphine." (lippincot, 137)

Inhibit release of gonadotrophin (LH, FSH, etc). Inhibits ovulation, reduces sperm count and testicle size. Chronic users are effected by this. Lippincot has a lot more to say about hormonal effects: "Morphine inhibits release of gonadotropin-releasing hormone and corticotropin-releasing hormone and decreases the concentration of leutenizing hormone, follicle stimulating hormone, adrenocorticotropic hormone, and beta-endorphin. Testosterone and cortisol levels decrease. Morphine increases prolactin and growth hormone release by diminishing dopaminergic inhibition. It increases ADH and thus leads to uurinary retention. (136)

Miosis (constriction of the pupils). This used to be a test of opiod use. It used to be that heroin abusers were tested with an antagonist injection that would make the pupils dilate if there was any heroin in the system -- they don't do it anymore, though, becasue it is too dangerous. The antagonist can potentially do more than just dilate pupils -- since heroin can be so dirty, who knows how it will cross-react. So today it is thought to be a bad idea. Good for drug administrators to know what exogenous chemicals are already in the patient's system. :-)) note - lippincot talks about ''pinpoint pupils,'' and how ''most other causes of coma and respiratory depression produce dilation of the pupil." (p.136)

Initially stimulates, then depresses vomitting center (CTZ). Be careful of giving these compounds in too great a dose in someone who just had belly stitched or chest closed. You really don't want people to vomit and re-open their wounds. Ouch.

All of these above effects are CNS actions. But, note that opiod analgesia occurs by both peripheral and central actions. (? not exactly sure what he's talking about here. but Lippincot p. 133-4 talks about distribution of opiod receptors)

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Cardiovascular effects of opiods:

- Peripheral vasodilation (histamine releasae) -- flushing of the face.

- Cerebral vasodilation (increase in intracranial pressure).The brain autoregulates its bloodflow independent of anything else. it must maintain consciousness. Lippincot says that increased cerebral vasodilation can lead to increased CSF pressure. "Therefore, morphine is usually contraindicated in individuals with severe brain injury." (p.136)

- Orthostatic hypotension. poeple need to get up slowly from their beds, when going upright from recumbant. Morphine depresses the protective reflex, and people can fall and get hurt.

G.I. Effects:

- increased tone, decreased activity. "In a word, constipation."

- Smooth muscle spasm like a charlie horse of the colon. This is rare, but it hurts. There are a number of sphincters in the body -- especially otie, the one in the gall bladder. This is the typical site for this kind of spasm. Remember that little tolerance ever develops to morhine's effect upon the GI tract.

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Tolerance and dependance. (regular use of opiods leads to this.

Tolerance: a decreased response to a drug with repeated use. Requires the presence of the drug - once you stop using the drug, the tolerance will abate and go away. Tolerance develops to most, but not to EYE or GI effects of opiods.

Phsical Dependence: (develops in the absence of the drug). The signs come once you go off the drug. You can seem fine as long as you are taking it. Defined by presentation of withdrawl signs. It develops concurrently with tolerance (albeit a different mecahnism). note that somewhere between 3-5% dentists will abuse drugs -- 2 or 3 of those in this room will become drug abusers. Vomitting, diarhea, "wet," is common in opiod withdrawl. Hardly ever leads to convulsions -- not going to be writhing on the floor. Most people coming home from hospital who had morphine for a while might have tolerance and dependance - - this can range from a cold to vomitting, diarhea.

Cross tolerance and cross dependence develop. you can use other types of miu agonists to satisfy tolerance/dependence.

Q: How long to get rid of tolerance? It varies.

Abusers -- choose their substance for sociological reasons as much as pharmacological effects.

Methadone is a miu agonist.

Heroin addicts -- withdrawl isn't what kills them. In an intitution they are often downgraded to methadone, and they have withdrawls from that instead. called a "methadone maintenance program."

The use of opiods in medicine is proven to not lead to addiction.

Miu opiod receptor agonists -- analgesics

- Morphine > morphine-6-glucuronide (M6G) -- this is thought by many to be the real analgesic; this metabolite. Oral morphine. No -- first pass effect uses 40-80% of it up. But since we have learned that you can titrate the dose and get arond the first pass effect. This is noce for chronic pain users, since then they don't have to keep administering pareterally. Some have an in-dwelling catheter, and they press a button that gives a smal, fixed dose. it has been shown that people who do this do a nice job of regulating their own doses. in this case there is a lockout amount that prevents you from overdosing, so patient is in charge only to an extent. But it is still effective. Takes patients away from being "clockwatchers," and then cursing at the nurse (as he demonstrated). Some have a pump implanted in skin -- a small osmotic pump, with an intraspinal catheter. They get a continuous infusion of morphine. Morphine can be administered into the brain ventricles. A catheter can be put right in -- uncommon, but it has happened. So, morphine can be effective by virtually any route of administration (even done by lungs in asia.) suppositories also works.

Codeine > morphine > M6G, PO, moderate pain. Codeine for mild to moderate pain. Used in cough medicines. Codeine is a common constituent in dentistry. Is codeine as effecacious an analgesic as morphine? YES. But is it used in the same way to kill pain as morphine? NO. It's just that codeine is put into preparations for mild to mofderate pain.

Heroin > morphine > M6G, IV, no advantage.

why heroin instead as others? Becasue it is more lipophilic. It can penetrate the brain more rapidly in the form of smoke, etc. Never found in clean form...

30% of people with cancer die in "moderate to severe" (in their own words) pain. This is hardly ever, ever necessary. This can be contolled with opiods. Every 3 or 4 years a congressmann will come along recommending heroin to use in health professions (often due to a personal experience of a loved one dying in pain due to terminal cancer).

So these above three are very similar pharmacologically. They all go to M6G. The big difference between them is that heroin is lipophilic (by the way, Lippincot says that "morphine is the lease lipophilic of the common opiods - p.136). Other than that, they are all prodrugs. There is no advantage to heroin...

Q: Heroin - is it THAT addictive? Pharmacologically, no. (Those drugs with most addiction liability are the ones that create euphoria). Some people do it recreationally on the weekends and it doesn't effect them through the week. Sociologicaly, yes; It is the other baggage with herion that makes it addictive.

Hmmmm - yet, Lippincot says that "Withdrawl [from morphine] produces a series of autonomic, motor, and psychological responses that incapacitate the individual and cause serious, almost unbearable symptoms." (138)

Other points from Lippincot: - "Morphine releases histamine from mast cells, casing urticaria, sweating, and vasodilation." It is contraindicated in athsmatics, since it causes bronchoconstriction.

- M6G -- note that M3G is inactive.

- OPIOD AGONISTS: Fentanyl, eroin, Meperidine, Methadone, Morphine, Sufentanil, Codeine, and Propoxyphene.

- OPIOD MIXED AGONIST-ANTAGONISTS: Buprenorphine, Pentazocine.

ANTAGONISTS: Naloxone, and Naltrexone.

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2/6/02 1:11 pm

Mu opiod receptor agonitsts - analgesics

There is no advantage to the use of heroin for the control of pain -- it;s justt tha t heroin is more lipophilic.

a miu agonist is a miu agonist is a miu agonistt

morphine > M6G, first pass metabolism, etc (see slide)

Codeine

Heroin

Mepeeridine - OB anlgesia (innitial claim that it waas free if addictiionio liabilityrnns outt to bee false). Meperidine is nice for OB becasue of short duration of action. But the critical reason is the meperidine does not readilly cross the placental barrier. This decreases likelihood of resp depression in the fetus.

peperidineeiiss iinitially synteiszed as an analogue of atropine) -- BUT IT DOES NOT END UP THAT way. It is an opiod.

Unlike the others, meperiedine can cause significant CNS stimulation

Methhadone -- good action when taken orally. Nice in this case for chronic cancer painn. But the problem is that its metabolites build up and contribute to sedation- this makes it a poor choice for ling term tx. So morphine is still better. There used to be methodone maintenance programs. µethosone maintenance clinics no longer exist as they used to. They discovered that it didn't do the trick for bringing people back to social normalcy.

Prophoxyphene (known as darvon) -- interesting because it isn't very efficacious as an analgesic. It will substitute as heroinand has beeen tried in maintenance programs. but no analgesia in typical doses -- no more than aasprin, or even more than a placebo. So why do people getpain relief from darvon? Answer: placebo effect (happens in 35-40% in pain trials -- make advanccing new ddrugs into the marketplace -- can be ahard for a new compound to prove to be etter than placebo!).. Do understand that darvon does have other efffects, though. can stimulate CNS.

Fentanyl -- described as ultra potent compared to morphine. But who cares? Potency isn't relevat, right? fentanyl isn't used as a general analgesic. One use is cardiothoracic surgery. Opiods don't' effect cardiac output. This is a real boon, since some general agents can cause trouble. But remember, fentanyl is an analgesic only, not an anesthetic. So occasionally you can wake up during procesure, or remember it afterwards when fentanyl is used. (WOW!). Fentanyl is very lipophilic. It has been made available as a patch. Can be nice post surgically or with chronic pain. It is even available as a lollipop (!). Used by cancer patients during "breakthrough pain," where pain breaks through when you are alreacy on mophine. You stick it under tongue and get god relief. So this was hard to get into market - tey have been available for 4 years. One of these days we might hear of a child that got ahold of it and died from it. So again, fentanyl is used for cardio surg, patch, and lollipop.

Two more agonists: Diiphenoxylate, Loperamide (in immodium) = antidiarhea. Used for travellers diarrhea. These are definitely miu agonists, but site of action is limitied to GI -- tey don;t go into systemic circulation. zthey will soono be available for topical application, inclusing scratched cornea.

MIXED AGONISTS-ANTAGONISTS

AGONIST EFFECTS AT THE KAPPA RECEPTOR, WHILE ANTAGONIZING MIU AGONIST AT THE MIU RECEPTOR. Why would this be a good thing? They presumably would not have abuse potential. Pentazicine was such a thing, and was advertized as not having abuse liability, and was not scheduled with other opiods. It was therefore easy to find, and was widely abused. It did indeed have abuse potential.

Pentazocine

Butorphanol

Nalbuthine

(all three of these are kappa agonists, miu antagonists). These three don't produce as much resp. depression, but they have analgesic ability. BUT what they don't tell you is that tey aren't as efficacious as the miu agonists. These compounds are fine for acute pain control. But they are not useful for long term chronic pain management.

Buprenorphine -- [artial agonist that isn';t used much.

pentazocine -- to prevent abuse, naloxone was mixed in with it.. naloxone is a universal opiod receptor antagonist, with preferential action at miu receptor, but blocks all receptors at sufficient doses. This interfered with euphoric effects when injected IV. But the naloxone has no effect when the altered pentazocine is taken intraorally.

Pain Therapy

"the single most reliable indicator fot te existence and intensity of pain - and any resultant effective discomfort or distress - is the patient's self-report."

Pain is highly subjective -- you cannot extrapolate your experience onto theirs. Your obligationi is to believe the patient when they complain of pain. You need to accept patient's complaints. Healt professionals typically UNDERESIMATE the amount of pain the patient is feeling.

Guage -- visual analogue scale -- for patients to report pain. As silly as it seems, it has incredible internal validity. Laws have been passed to have nurses, etc, regularly have patients rate their own pain. 4-5 is high doscomfort. 9 is very serious. Nursing staff in a study consistenly rated patient pain 2 notches lower than it really was. Also, professionals underestimate doses needed. In one study it was 25-50% less. So imagine your frustration in a hospital setting with pros that won't give you enough meds and who are underestimating your level of pain.

Also, health professionals are opiophobic. They are always conscious of opiod prescriptions always looking justifiable, to keep the DEA away. Basiacally, if you give tylenol 3 after extraction, you're fine. but if you give it out over a period of months, or opiods for TMD, you can get into trouble. Unless you specialize in pain control, be careful with this stuff.

Acute opiod intoxication:

sedation > stupor (as content in bloodincreases) > coma

they have pinpoint pupils, and resp system is depressed.

So these are the three cardinal signs of opiod intoxication: stupor + pinpoint pupils + resp. depression. There will be a test on this. Know these three cardinal signs. Constipation doesn't count. These carsinal sign are for intoxication.

how to reverse intoxication? Naloxone. But as we discussed before, it must be given parenterally. Remember that duration may be extended -- morphine overdose. Two reasons to re-administer naloxone: 1) the morphine dose will be greater than normal, 2) it as a shorter duration of action.

Used to bring a dog into class -- give morphine -- the cardinal signs would appear. hen they would give naloxone and watch th esymptoms reverse. "This suff is magic in reversing intoxication"

when taken by mouth pentazocine is analgesic, but when administered parenterally, it creates euphoria, so then it gets abused. These are weak antagonists. Don't be confused about thiss (hmmm.)

Naloxonoe is a pure antagonist, working at all opiod receptors. Works parenterally, not orally.

Naloxone --

- pure antagonist

- no effect orally

- effective parenterally

- talwin-N (pentazocine) -- problem: how to prevent abuse potential so it doesn't get pulled of the market. So idea -- add naloxone, then it won't work parenterally, but the talwin will still work orally. So it's a simple idea. So the naloxone is only to prevent parenteral misuse. (Q - then why not take talwni orally? becase doesn't get you uhigh that way. You won't get instant euphoric effect. Alcohol is the only case, pretty much, where drugs are abused orally.

Q - what if you volatilize it? A: I have no idea. I've never heard of "crack tolwin." "that's a first -- that's the first time anyone has asked that. this is an interesting class.

drug classes used as analgesics (think of the market value of analgesics -- this is huge. gotta be projected to create a million bucks to even go forward. Witness viagra. There is a big pie at stakewith analgesics. NSAIDS are where most people are trying to break in)

- opiods (mophine, codeine)

- NSAIDS

asprin - from willow bark (which was known as an analgesic and fever reducer)

- so NSAIDS have analgesic, antiinflammatory, and antipyretic effects. They are comonly used in conjunction with opiods. They are maybe even more widely used as intionflammatory drugs, esp. for arthritis. (doesn't cure, however). Also nice for sprain, TMD, etc. Resucing inflammation can contribute to pain relief in and of itself. Last, they are antipyretic -- asprin won't change the set point of body temp, but will reduce it if it is too high.

- widely used for chronic tx -- 14 million regular users in U.s.

- Not as good as analgesia as opiods.

- mechanism = inhibition of cyclooxegenase (COX), of which there are two isoforms: COX1 and COX2

- asprin is prototpe.

see cartoon slide for mechanism of action. First arachasonic acid becomes available after tissue insult. COX takes arachadonic acid to -- etc... note that this diagram is limited. there are other liipooxygenases, but they aren't relevant for this discussion.

prostoglandins are important to protecting stomach lining. So when you inhibit COX1 you do put your stomach at risk, cause it can't protect gastric mucosa as well.

Understand that COX2 can also play a role in protecting gastric mucosa.

NSAIDS do not affect lipoxygenase. Their principle action is to interefere with COX.

Actions of COX products:

- renal blood flow > renal ischemia

- gastric mucous > irritation. regular dose of asprin will priduce occult blood in stool.

- platelet aggregation > bleeding (clotting dysfunction). can be useful prophylactically with those who are at higher risk for thromboembolic events -- 50-75 milligrams per day is a prophylactic dose. This is fairly common for men and women 40-45 years and older. This effect will linger for 7 days, since that is the life cycle of platelets. Gotta stay off asprin before surgery) Note that asprin has potentially serious effects. Have lots of water with it.

- uterine contractions > delays labor. note that uterine cramping during mentruation is due to prostaglandins.

- inflammation > leukotrienes and some other sytokines aren't effected, but in general nsaiids work well.

- nociceptor sensitization > analgesia

- hypothalamus > reduce fever

So NSAIDS can cause problems with all these things. Can bee irreeversible in its effects upon kidney. It is important to dring=k a lot of water with them. nephrotoxicity. seattle seahawks player -- now on dialysis.

Over time, there can be an overall body load of NSAIDS (salicylates) that can lead to nephrocity (?). So this has been comcluded post hoc, so there is no prospective evidence of kidney problems and ulcers. There is HUGE variability between individuals who take NSAIDS. In all cases it wise to protect kidneys and GI with lots of concomittant water.

Summary slids: COX1 and 2 effects. COX1 leads to renal and platelet fx, and protects gastric mucosa, and brain and kidney.

COX2 effects pain and inflammation. It is believed that when tissue is injured, COX2 is induced, and creates more prostenoid products than COX1.

Prinicpally NSAIDS were sold as antiinflammatory...

COX2 inhibitors could be huge, becuase they wouldn't lead to the GI upset, and since they are COX2 cause the principally mediate pain and inflammation.

marketing... example: IBS (irratable bowel syndrome). Drug was marketed to fix this. But many of these people developed ischemic bowel (!). This was terrible, but it happened at such a low incidence that it could not have been forecasted in a trial!! (that's something to remember). with all that said, we are finding that the COX2 inhibitors aren't so magic. but te industry is still trying to introduce new COX2 inhibitors, since the theory is that they are more selective for pain and inflammation, without GI problems. That would be great, and we will be inundated with companies that are trying to find this.

theraputic applicationis of NSAIDS

- rheumatoid and osteoarthritis -- 3-6 grams daily asprin dosage (GRAMS!)

- prophylaxis against platelet aggregation (asprin, 50-75mg daily)

- analgesia (mildto moderate pain, dysmennorhea)

- fever

General pharmacology

- repid GI absorption

- high protein binding (displacement of bound drugs)

- hepatic metabolism, renal excretion.

NSAIDS can lead to a different action, or heighten the action the action of other drugs that are bein taken.

Significant adverse effects -- see slide. Heck - asprin might not even pass muster with the FDA today.

2/8/02 1:10 pm

NSAIDS IV

salicylates - asprin (ASA), methyl salicylate, diflunsinal

- [heck -- ust see slide -- I'm behind so I'll start typing where he is talking.]

others -- phenylbutazone: like endomethicin in that it is used when other antiinflamms don't work. Prohibited in horses, not in humans. leasds to alteration of formed elementsin blood, leading to aplastic anemia. So if you take this you need regular blod screening.

- acetominophen (tylenol) -- "NSAID-like." Not a true anti inflammatory. Should not be used for arthritis, etc. Nice to put in to syrups for kids, since it;s harder to give asprin to children. Can lead to sgnificant liver damage in Overdoses. (significant hepatotoxicity).

- COX2 selective copmunds (talked about these at the end of last period) --

-- celotoxib -- (get info on this)

-- rofetoxib... Both of these are supposed to not lead to gi problenms. Another problem -- COX 2 is expressed in the brain. So inhibiting it might have some negative consequence. COX2 inhibitors are being tested for a variety of other things, as well. They have been shown to have tunor suppressing ability. how? we don;t know.

advantage of ibuprofin over asprin: some people don't tolerate asicylates well. So ibuproin can help in that regard.

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DRUG ABUSE...

Psychological dependence, physical dependence, and tolerance represent states of adaptation.

Psychological dependence: (habituation) -- drive to take drug for its psychoactive effects. We are all psychologically dpendant upon habitual behaviors... a TV show is an example. Some people might be really upset to miss an exposure to something (like a tv show or a cup of coffe with newspaper in the morning)

Addiction: behavioral pattern of compulsive drug use (overwhelming involvement with obtaining and using the drug; high relapse)

Physical dependence: (develops in the absence of the drug) -- defined by presentation of withdrawl signs.

Tolerance: (requires presence of drug)-- decreased response to a drug with repeated use

Tolerance and dependence are reversible. (and there is cross-action: a mui agonist is a miu agonist is a miu agonist.)

Characteristics of abused drugs (see slide)

anxiolyitcs -- like benzodiazapemes.

PCP -- was called hog. Activates sigma receptor. Sigma is not an opiod receptor per se, but opiods can act on the sigma receptor to creat dysphoria.

Inhalants are very dangerous -- lack of O2

Which of these compunds are the worst? Which are really bad, and which aren't so bad? Which would I abuse vs. another. Gotta look beyond just tolerance, phys and psych dependence.

Wat kind of hazard do these pose to the user? And to society at large? For example. alcohol is legal, but has direct toxicity and definitey kills -- through driving especially. every time you drink you might be killing neurons.

slide: hazards of abused substances.. (this is personal -- you might have a different interpretation) the high hazards substances basically turn abusers into psychotic people.

This is a big issue with sociological ramifications