2Early antipsychoticsName all of the prototype 1st generation antipsychotic agents (7)Thioridazine, chlorpromazine, thiohixene, fluphenazine, loxapine, haloperidol, and molindoneWhich one is the aliphatic derivative? The piperidine derivative? The piperazine derivative?ChlorpromazineThioridazineFluphenazineWhich one is the thioxanthene? The Butyrophenone? The dibenzoxazipine? The dihroindolone?ThiohixeneHaloperidolLoxapinemolindone
3Indications and Effects What are the clinical indications of the 1st generation “typical” antipsychotics?Schizophrenic (or otherwise psychotic) patients, for antiemetic properties, and to stop hiccupsWhich of the typical antipsychotics are most effective?They are all equally effectiveWhich are the most potent? The least potent?The butyrophenones and piperazine derivatives are the most potent (haloperidol and fluphenazine)The aliphatic and piperidines are the least potent (chlorpromazine and thioridazine)What receptor mediates the activity of these compounds?Activity occurs through antagonism at the D2 dopamine receptorHow do these drugs prevent nausea and emesis? Which drug is NOT anti-emetic?The antiemetic properties of these drugs are mediated through blocking D2 receptors in the emesis chemoreceptor trigger zoneThioridazine has no significant anti-emetic activity
4GroupsAmong this drug class, how is potency of the drug correlated with degree of extrapyramidal symptoms?Higher potency seems to correspond with higher levels of extrapyramidal side effectsWhat three other receptors are blocked by some of these drugs? What group (generally) has more of these effects?Some of the 1st generation antipsychotics are also effective blockers of alpha adrenergic receptors, muscarinic cholinergic receptors and histamine receptors.In general the lower potency antipsychotics have greater activity at these other receptor sitesWhich drug (listed) is commonly used for intractable hiccups?chlorpromazine
5Mechanism and Pharmacokinetics Which of the brain’s dopamine systems is associated with the antipsychotic effects of these agents? Which dopamine system is affected to cause the extrapyramidal effects?Blocking dopamine receptors in the mesolimbic-mesocortical systems results in the antipsychotic activityBlocking dopamine receptors in the nigrostriatal system mediates the extrapyramidal effectsAntipsychotic activity is mediated through which subtype of dopamine receptor?The D2 subtypeRate these drugs as a group on oral availability, first pass effect, protein binding, and lipid solubility.Put simply, they have a lot of all of that except for oral availability, which is poor with incomplete absorption. They are pharmacokinetically crappyWhich two groups have active metabolites?Aliphatics and piperidines (chlorpromazine and thioridazine)
6Adverse Effects—Motor What motor adverse effect is common with the 1st generation antipsychotics in the first 5 days? Describe the syndrome. How is it treated?Acute dystoniaSpasms of face, neck, and backTreated with anticholinergicsWhat motor adverse effect is common with the 1st generation antipsychotics between days 5 and 60? Describe the syndrome. How is it treated?Akathisiais a syndrome characterized by unpleasant sensations of "inner" restlessness that manifests itself with an inability to sit still or remain motionless, hence its origin ancient Greek α (a), without, not +(káthisis), sitting] –http://en.wikipedia.org/wiki/AkathisiaTreat by lowering the dose and/or administering anticholinergicsWhat motor adverse effect is common with the 1st generation antipsychotics between days 5 and 30? Describe the syndrome. How is it treated?(drug induced) parkinsonismLooks like parkinson’s disease
7Even more side effects Describe the perioral tremor and its treatment. The “rabbit syndrome” involves tremors around the nose and mouth and can occur months or years after beginning treatment with antipsychotics. It is treated like the others, with lowering the dose and/or anticholinergicsThe secretion of which hormone is increased by 1st generation antipsychotics? Which two hormones are decreased?Hyperprolactinemia occurs with these drugsDecreased gonadotropin and estrogen release
8Way more side effectsDo first generation antipsychotics cause edema or weight gain?Yes, bothWhich anti-psychotics (potency) cause more sedation?The lower potency anti-psychotics cause more sedationWhich 1st generation antipsychotic is best to use in a patient with a history of seizures?In general, these drugs lower seizure threshold and should be used carefully in patients with a history of seizures. Fluphenazine is the best choice in these patients.What is neuroleptic malignant syndrome? What is its mortality? How is it treated?A rare but life threatening condition which resembles a very severe form of parkinsonism with catatonia, autonomic instability (BP, pulse, temp), stupor and possibly myoglobinemia.Mortality is >10%Treatment includes discontinuing the antipsychotic and adminstering dantrolene, along with supportive care
9More bad stuffWhich autonomic receptors are commonly blocked by antipsychotics?These drugs can block both the alpha-adrenergic receptors and the muscarinic receptors, causing a variety of problems including urinary retention.What effects do first generation antipsychotics have on the skin?They cause both a blue-gray skin discoleration and a photosenitivity that resembles a severe sunburn.Name three drug interactions of 1st generation antipsychotics.They potentiate the effect of CNS depressants, opioids, and antihistaminesThey reduce the effectiveness of L-dopa in patients with parkinsonism (antagonism)They have additive anticholinergic effects with tricyclic antidepressantsHow does a physician choose between the various antipsychotics in determining which drug to give a patient?The selection of an agent often depends upon the side effects and the ability of the individual patient to tolerate them
10Atypical Antipsychotics and Lithium January 29, 2008“I’m so happy‘cause today I found my friends,they’re in my head.I’m so ugly,that’s ok ‘cause so are you.”
11Clozapine For which patients is clozapine approved? Clozapine is only approved in patients suffering from schizophrenia who are refractory to more traditional antipsychotics.How potent is clozapine?2x potent as chlorpromazine, (low potency)What makes clozapine’s side effect profile superior to other antipsychotics? What pharmacologic difference might account for this?Clozapine does not produce severe extrapyramidal dysfunction nor hyperprolacinemiaClozapine has a relatively low affinity for D1 and D2 receptors and is more specific for D4Also, chronic treatment does not result in an increase in the number or sensitivity of dopamine receptorsWhat non-dopamine systems are affected by clozapine?Clozapine causes changes in alpha adrenergic and muscarinic receptors, as well as blocking serotonin (5HT-2 rec) receptors.
12Just a few side effectsWhat is the half life of clozapine? Which patients get higher plasma levels?Half life is 12 hoursYoung, women who smoke get higher plasma levels than older, non-smoking men.What are the most common side effects of clozapine? What are the dose limiting side effects? What is the unique nighttime clozapine side effect? What adverse effect delayed its approval in the USA?Sedation, fatigue, weight gain, and diabetes are common.Nausea and vomiting may limit the dose.Clozapine also causes excess salivation and severe drooling on your pillow at night time.Potentially fatal agranulocytosis (1-2%, requires frequent blood tests)What percentage of patients on clozapine develop new onset seizures?2-5%For what patients is clozapine contraindicated?Any patients with any kind of bone marrow problem or leukopenia, or who are taking anything else that may affect the bone marrow (carbamazepine)
13The other atypicalsName the four mixed antagonist atypical (2nd Generation) anti-psychotics.risperidone (risperdal), olanzapine (zyprexa), quetiapine (seroquel), and ziprasidone (zeldox)Brand names are listed parenthetically just because the BS people use them some of the timeAll of these drugs antagonize D2 dopamine receptors, but what else do each of these drugs do? What is the half life of each drugRisperidoneBinds D2, 5-HT2, alpha adrenergic and histaminic H120 hours (w/active metaboliepaliperidone)Olanzapine5-HT2, 5-HT3, 5-HT6, D1, D2, D4, H1, α-1, and muscarinic M130 hoursQuetiapineHas a higher affinity for 5-HT2 than D26 hoursZiprasidoneD2, 5-HT2, H17 hoursHow are these drugs absorbed orally?wellWhich is the only of these drugs that has an active metabolite?Risperidone (paliperidone)
14Side effects for daysWhat are the most common side effects of risperidone? What are the initial side effects (elderly)?Asthenia, insomnia, difficulty concentratingOrthostatic hypotension and reflex tachycardiaOf the atypical antipsychotics, which has the highest incidence of extrapyramidal effects? Which causes the most hyperprolactinemia?RisperidoneWhat are the main side effects of olanzapine?Postural hypotension, somnolence, constipation, weight gain, diabetes, dizziness, sexual dysfunction, and akathisia (these are pretty much the normal atypical antipsychotic side effects)Which two atypical antipsychotics cause the most weight gain?Clozapine and olanzapineWhat are the strange and different adverse effects of quetiapine?Increased serum aminotransferase, cataracts (in dogs)Which atypical antipsychotic causes the greatest elongation of the QT interval? What does this drug cause the least of?Ziprasidone (so don’t use it with other QT prolonging drugs or arrhythmia pts.)Of the atypical antipsychotics, ziprasidone causes the least weight gain.
15AripiprazoleWhat drug causes marked decrease in the clearance of quetiapine?PhenytoinHow do the newer drugs stack up against haloperidol?Risperidone and olanzapine have been shown to be at least as effective as haloperidolWhat is the prototype partial agonist antipsychotic?AripiprazoleFor what is aripiprazole useful?Equally useful as haloperidol for antipsychosis, aripiprazole is also useful in acute manic episodesWhat is the mechanism of aripiprazole?Partial agonist at D2 and 5-HT1a receptors and antagonist at 5-HT2a receptorsIs a “dopamine system stabilizer” in that it maintains a medium amount of D2 activationWhat is the half life of aripiprazole? In what patients can this be longer?75 hoursIn patients with variation in the CYP 2D6 system, the half life can be 146 hrs.
16More aripiprazole and conclusions What are the side effects of aripiprazole?Anxiety, headache, nauseas and vomiting, constipation, insomnia and somnolence, lightheadednessNo extrapyramidal effects, hyperprolactinemia, hyperlipidemia, hyperglycemia, or weight gainName three CYP 2D6 inhibitors. What should be done with aripiprazole if coadministered with any of these drugs?Fluoxetine, paroxetine, quinidineThe dose of aripiprazole should be reduced if coadministered with any of the aboveWhy isn’t aripiprazole the only antipsychotic used by now?While it is effective in treating schizophrenia without causing extrapyramidal symptoms, weight gain, hyperprolactinemia, or hyperlipidemia, aripiprazole has not been on the market long enough to evaluate its long term safety.What are the differences between 1st and 2nd Generation antipsychotics?They are roughly equally effective in treating psychosisFirst generations have a higher incidence of extrapyramidal effects, while second generation have a higher incidence of weight gain, hyperglycemia, and hyperlipidemiaSecond generation drugs are about 10x as expensive
17Lithium CarbonateHow long does it take for lithium carbonate to work? What percentage of patients get their mood stabilized?2-3 weeksNormalizes the mood of 80% of patientsWhat do you do if a patient is suffering from “an acute manic attack” currently?Use an antipsychotic first, then introduce lithium later as the patient becomes stabilizedThe low therapeutic index and severe toxicity of lithium require a cooperative and stable patientCan lithium be used in patients with recurrent depression without mania?According to this lecture yes, but it is much more dangerous than the SSRIs.What is the current best guess as to the mechanism of lithium?Downregulation of second messangers IP3 and DAG is currently considered the best possibility.Other hypotheses include effects on ion transport or on serotonin and dopamine systems.What is the half life of lithium?About 20 hoursWhat is the therapeutic window of lithium?0.9 to 1.4 mEq/L
18Lithium toxicitiesAt what dose of lithium is toxicity first noticed? What is the treatment for lithium toxicity?1.5 mEq/L (severe toxicity at 2.0 mEq/L)There is no specific treatmentWhat three toxicity symptoms are diagnostic of lithium toxicity? What other symptoms occur?Coarse tremor, hyperreflexia, and slurred speechVomiting, profuse diarrhea, arrhythmia, hypotension, ataxia, mental confusion, cranial nerve and focal neurologic deficits, coma, convulsions, deathWhat side effects are common at therapeutic doses?Nausea, diarrhea, drowsiness, hypothyroidism, polydipsia and polyuria, weight gain, cognitive blunting, birth defectsIs lithium secreted in breast milk?YesIn which patients should lithium be used “with caution”?Patients needing a low sodium diet and those in the first trimester of pregnancy
19Other Drugs What are two alternative drugs for bipolar disorder? Carbamazepine and valproic acidWhy isn’t carbamazepine a great choice?A controlled study in the VA system has shown it to be ineffective.Why might you use valproic acid (Depakote) instead of lithium?It appears to be as effective as lithium in the early weeks of treatment, it has fewer side effects, and the dose can be titrated up more quickly.Long term efficacy has not been determined.
20Dementia How many americans are affected by dementia? 4.5 million americans100 billion dollars annuallyWhat is dementia?An acquired persistent and progressive impairment in intellectual function, with compromise in at least one other cognitive domain (below) that impairs daily living.Language, visuospatial, calculation, judgment, problem solvingWhat are the three most common forms of dementia in order of most to least?Alzheimer’s (60-80%), vascular dementia, lewy body dementiaWhat neurotransmitter deficiency is theorized to be critical in the genesis of alzheimer’s disease? Where is one place in the brain that is particularly affected (loss of neurons)?AcetylcholineNucleus basalis of meynert, which is the major source of Ach to the cortex.Name the cholinesterase inhibitors.Tacrine, donepezil, rivastigmine, galantamineName the NMDA receptor antagonist.MemantineName all the other drugs that are FDA approved for the treatment of Alzheimer’s disease.There are none
21Alzheimer’s Disease What is the first clinical feature of Alzheimer’s? Impairment of short-term memoryIs a deficiency of acetylcholine critical in the genesis of the symptoms of alzheimer’s disease?According to the cholinergic hypothesis, yes.How does Tacrine funciton?Centrally acting, noncompetitive, reversible cholinesterase inhibitorAlso blocks reuptake of dopamine, NE, and serotonin. Inhibits MAOBlocks sodium and potassium channelsPartial muscarinic agonistWhat is Tacrine’s half life?2-3.5 hoursWhat is the most important adverse effect of Tacrine? What adverse effects are common?50% of patients get hepatic toxicitySLUD- salivation, lacrimation, urination, defecationNausea, vomiting, diarrhea, headache, myalgia, ataxia
22Donepezil How does donepezil work? What is donepezil’s half life? Noncompetitive, reversible inhibitor of acetylcholinesteraseWhat is donepezil’s half life?70 hoursWhy is donepezil better than tacrine?Donepezil does not cause hepatic toxicityWhat type of inhibitor is rivastigmine?It is a “carbamate” inhibitor of acetylcholinesteraseIt is thus metabolized by acetylcholine to a decarbamylated productWhat are the adverse effects of rivastigmine?Nausea, vomiting, diarrhea, abdominal pain, anorexia, weight lossNo hepatic toxicity
23GalantamineUse some crazy chemestry words and a flower to describe Galantamine.It is a tertiary alkaloid and phenanthrene derivative extracted from daffodial bulbsDescribe the mechanism of Galantamine.Reversible, competitive inhibitor of central acetylcholinesterase.Also a nicotine receptor agonist (unknown significance)What liver system metabolizes Galantamine?CYP 2D6 and 3A4 (can get toxicity in patients w/o 2D6)What unique side effect does Galantamine have?In this class, it’s the only one listed to cause bradycardia. Other side effects are typical for a AchE
24MemantineWhat patient population (severity of disease) are helped by Memantine?Moderate to severe Alzheimer’s disease patients are helped by memantine.Describe the mechanism of memantine. Why does this help?Noncompetitive NMDA receptor antagonist. It is thought to prevent NMDA calcium channel opening at high firing rates (but not at lower, normal rates)Excess NMDA activity is thought to be toxic to neurons, and to play a role in dying neurons reaching out and hurting their neighbor neuronsWhat clinical benefit does memantine cause? What is its half life and elimination mode?Some reduced rate of cognitive deterioration (maybe)60-80 hours, excreted in urine.Describe memantine’s side effects?Dizziness, headache, constipation, hallucinations, confusion
25Other stuffWhich of the vitamin, antioxidant, and ginko biloba “medicines” have been shown to help with Alzheimer’s disease?None of themWhat molecule is the toxic end product of beta secretase and gamma secretase cleavage of APP?Aβ-42Do we have any useful inhibitors of beta secretase or gamma secretase?NopeDo antibodies to Aβ induce clerance of the molecule? What bad thing happened in the (human) clinical study?Yes, in a mouse model anyway.Caused meningoencephalitis in 6% of patientsHow awesome is Etanercept?Super awesome
26Pharmacologic Management of Parkinsonism and Huntington’s
27Parkinsonian basicsIn parkinson’s, symptoms start ______ and become _____.Unilateral, bilateralWhat are the three diagnostic symtpoms of parkinson’s?Tremor (pill rolling, non-intention), rigidity (cogwheel), bradykinesia/akinesiaWhat percent of adults over age 65 will get parkinson’s (idiopathic)?About 1 percentWhat drugs cause drug-induced parkinsonism?MPTP, antipsychotic medicationsWhat role does acetylcholine play in parkinson’s?Dopamine typically inhibits ACh excititory neurons, decreased dopamine causes an imbalance in this system.This is the rationale for the use of anticholinergic agents like ____ and ____.trihexyphenidyl and benzotropine
28Stages and Types What are the stages of parkinson’s disease? Unilateral symptoms, tremor of one upper limb, slight lateral tilt of upper body away from affected side, reduced arm swing, cogwheel.Bilateral symptoms, stooped posture, more apparent motor symptomsShuffling gate becomes severe (falls)And 5. continual decline in functionWhat are the four types of parkinsonism?Postencephalitic parkinson’sIdiopathicDrug inducedMiscellaneous (??)
29Medications What were the first drugs used against parkinsonism? AnticholinergicsFor whom are these medicines still used?Anticholinergics are used for psychotic patients (who shouldn’t take L-dopa) and for drug induced parkinsonism. They are also used in combination with L-dopa in some patients.How long is the half life of L-dopa?3 hours, metabolized to dopamine (peripherally)What is the high end of the dosing spectrum with L-dopa?At least 8-10 grams per day can be used.How do you prevent or limit side effects?By titrating the dose up very slowlyWhat side effects are common with long term use of L-dopa?Choreiform movements, mental confusion, deliriumN & V, orthostatic hypotension, arrhythmias also occurN & V or N/V is nausea and vomitingWhat drug interactions with L-dopa are problematic? Which one is useful?MAOinhibitors (hypertensive crisis) and antipsychotics (antagonism) are contraindicated, pyridoxine (B6) causes rapid metabolism of L-dopa.Carbidopa coadministration increases the percentage of L-dopa that crosses the BBB, reducing the necessary dose of L-dopa 7-10 fold.
30ErgotsHow well does amantadine work for parkinsonism? What is it normally used for? What are its side effects.Only useful for a couple of weeksAmantadine is an antiviral agent that also causes release of dopamine from dopamine neurons and has a little NMDA antagonism (half life 2-4 hours)Headache, confusion, and hallucinationsWhat is the mechanism of Bromocriptine and Pergolide? What is the difference in their mechanisms?These drugs are direct acting dopamine agonistsBromocriptine is an agonist at D2 but an antagonist at D1, pergolide is an agonist at D1 and 2.How are these drugs used?Bromocriptine or pergolide can be used alone or with L-dopa or with L-dopa + carbidopaPergolide may have a better benefit to risk ratio (or not)Why isn’t pergolide on the test?It causes a 6-fold increase in heart valve problems or something like thatWhat is bromocriptine metabolized to?L-amphetamine and L-methamphetamine (which are much less potent and the D isomers)What are the side effects of bromocriptine?Raynaud like digital spasms, abnormal choreiform movements, dyskinesias, mental confusion, delirium, hallucinations, and depression, postural hypotension, premature atrial contractions, sinus tachycardia, and angina. Also nausea and vomiting. Sounds fun.In whom is bromocriptine contraindicated? What is the other limiting factor?History of psychotic illness, recent myocardial infarction, peripheral vascular disease, and peptic ulcersCost- it is very expensive
31What are the newer dopamine agonists? Pramipexole and ropiniroleWhy are these better than the ergot derivatives?They are better toleratedWhat strange effect sometimes happens with these new dopamine agonists?Falling asleep during normal daytime activitiesHow does Selegiline work? Why is this good?It inhibits the B form of MAOThe drug leaves the A form of MAO alone, which prevents the problem of hypertensive crisisAlso some studies indicate that these drugs actually reverse some of the damage in parkinson’s disease
32Yo-yo-yoing holidaysWhat are the names of the (reversible) COMT inhibitors used?Tolcapone and EntacaponeWhat are these drugs used for?They are used as adjuvant therapy to increase the “on time” of the L-dopa (in patients with “wearing off”)What is this wearing off business? How is it treated?Some patients who take drugs every 6 hours get return of symptoms at 4-5 hours, thought to be caused by decreased central conversion to dopamine and decreased dopamine storage.Also known as “end of dose deterioration”Obviously, the easy way (for the doc) is to just make the patient take the medicine every three hours (at half the dose).What is Peak dose dyskinesia? How is it treated?Abnormal, involuntary movements which occur 1-2 hours after dosing. May involve excess dopamine)Smaller and more frequent dosesWhat is yo-yo-ing?Patients cycle back and forth in 30min intervals of doing well and doing poorly. This effect is not understood and is not related to dosing frequency or size.Thought to be caused during a point where disease process is almost too severe to be relieved by drugs anymore.How useful are drug holidays?Not shown to be helpful
33Huntington’s Chorea How many people get Huntington’s? At what age? 1/50,000Age yearsWhat are the early symptoms of Huntingtons?catatonia, aggressive outbursts, psychotic behavior, exaggerated reflexes, good muscle strength, but weak toneWhat are the later symptoms?Progressively worsening dementia, increased appetite without weight gainWhat are the final stage symptoms?Greatly increased diet with weight loss, rigid motor tone, death within years of onset of symptomsWhat drugs improve the motor symptoms of Huntington’s?Reserpine, phenothiazine and butyrophenone antipsychoticsWhat drugs make the motor symptoms worse?L-dopa, anticholinergics, and dopamine agonists
34Non-steroidal Anti-inflammatory Drugs February 4, 2008
35What is the mechanism of the NSAIDs? They all inhibit cyclooxygenase and subsequent prostaglandin and thromboxane synthesis.They do not inhibit the leukotriene pathway. Shunting of arachidonic acid to the leukotriene pathway has been hypothesized as a mechanism of toxicity and anaphylaxis.What’s the difference between COX-1 and 2Cox 2 is an inducible form, whereas Cox-1 is present in every cell. Major sites of Cox-1 that result in toxicity are:Platelets, blood vessles, stomach, kidneyTheoretically, why are COX-2 inhibitors better than regular NSAIDs?They don’t cause problems in places listed above.
36What effect do prostaglandins have on pain? Prostaglandins decrease pain thresholdWhat severity of pain are NSAIDs useful for?Effective against mild to moderate and dull aching pain, though they can be as effective as opiates in certain types of painIn jaw and mouth surgery NSAIDs are just as effective as opiatesHow do NSAIDs cause anti-inflammatory effects?Inhibiting PGE2 and PGI2 reduces edema formationAt high concentrations NSAIDs reduce neutrophil migrationWhat mediates NSAIDs antipyretic effect?NSAIDs prevent PGE2 formation, which is believed to be responsible for altering the body temperature set point
37Side effects What are NSAIDs used for? Pain, primary dysmenorrhea, joint inflammation (side effects are a problem when used for inflammation in rheumatism), fever, sunburnWhat is the first line drug of choice for rheumatoid arthritis?Aspirin in high dosesWhat are the most common side effects of the NSAIDs? What causes these problems?GI distress, damge, bleeding/ulcerationProstaglandins PGE2 and PGI2 decrease acid secretion and increase mucous production. NSAIDS decrease the formation of these prostaglandins and increase the likelihood of GI problems. Chronic use results in erosion of the stomach liningWhat mediates NSAID renal effects?PGI2 and PGE2 cause vasodilation of the afferent arteriole, which promotes GFR. NSAIDs decrease production of these chemicals and decrease GFR.What mediates NSAID effects on platelet function and bleeding?TXA2 makes platelets “sticky,” and is a potent vasoconstrictor (procoagulant). Epithelial cells produce PGI2 in response to platelet activity, which inhibits platelet aggregation. NSAIDs inhibit platelet TXA2 and PGI2 production, which can cause a net increased bleeding time.
38Salicylate What is the prototype Salicylate? How does it work? AspirinIt is an irreversible inhibitor of prostaglandin synthesis (binds COX nonselectively and irreversibly)What is special about aspirin’s nonreversible mechanism?Since aspirin binds COX irreversibly, it permanently reduces a platelet’s ability to aggregate. It’s effects on epithelial cells are minimal, however, as epithelial cells can make new COX.What is aspirin metabolized to? How long is aspirin’s half life? What kinetics does aspirin follow?Salicylic acid (the active agent)15 minutes (salicylic acid has a half life of 3-4 hours)First order at low doses and zero order at high dosesHow does pH affect the distribution of aspirin?Decreased pH increases unionized drug available for distribution. Aspirin makes the blood more acidic.
39Aspirin toxicitiesWhat aspirin toxicity is common at higher therapeutic doses (2-4 g)? mild toxicity at 6-8g? Moderate toxcity at 8-10 g? Severe intoxication at g?Bleeding, decreased uric acid excretion, hypersensitivity reactionsSalicylism, tinnitus (early warning sign), increased metabolic rate (uncoupled mitochondria) with consequent fever, hyperventilation and respiratory alkalosisModerate toxicity causes respiratory depression with respiratory, chemical, and metabolic acidosis (which is exacerbated by the previous alkalosis).Severe toxicity involves wild pH, hyperthermia, dehydration, loss of electrolytes, and is life threatening (coma, renal and respiratory failure).How does one treat salicylate intoxication?Cool, rehydrate, correct acid base and electrolyte imbalancePrevent further absorption (emesis/lavage)Alkalinize the urine to increase excretionHemodialysisDiazepam for convulsions
40NSAID varieties For whom is aspirin contraindicated? Patients with: renal disease, bleeding disorders, hypersensitivity, gout, and young children during or following a viral infectionIs ibuprofen another NSAID? How effective of an analgesic is it? Of an anti-inflammatory? What are ibuprofen’s side effects?YesAt low dose, it is more effective than aspirin at analgesiaAt high doses, its anti-inflammatory action is just as good as aspirinGI irritation and bleeding, rash, tinnitus w/dizziness, agranulocytosis, aplastic anemia, renal failure, interstitial nephritis, nephrotic syndrome.What’s good about Naproxen? What’s bad about Naproxen?Long half life (13 hours)Intermediate potency (<ibuprofen or aspirin)Has increased incidence of side effects (GI pain most common) compared to ibuprofen, likely due to need for increased doseWhat is the most potent NSAID? What is it used for? What are its major toxicities? Half life?IndomethacinUsed for acute gout, spondylitis, osteoarthritis, and is the drug of choice to close a patent ductus arteriosisHigh incidence of GI distress and other toxicities (25% of patients will discontinue)4-5 hours
41What is ketoralac used for? Ketoralac is the only IV NSAID. It is used for short term pain managemement, can be used to replace morphine in certain conditions but is often used with an opiateWhat are COX-2 inhibitors used for?RA, OA, acute pain, dysmenorrheaWhat happened to the COX-2 inhibitors?They are prothrombotic, and in clinical trials they have been shown to cause a 2-4 fold increase in the incidence of cardiovascular side effectsIt is suspected that selective COX-2 inhibitors have selective inhibitor activity against prostacyclin (PGI2) synthase (as opposed to TXA2). This makes them prothrombotic.What is Meloxicam?It is a partially selective COX-2 inhibitor with a 20 hour half life
42What drugs are used to prevent gout? What is gout?Gout is a metabolic disorder characterized by hyperuricemia and deposition of monosdium urate in the tissues, particularly in the joints. Inflammation is triggered by the actions of the infiltrated granulocytes.Granulocytes release lysosomal enzymes and inflammatory mediatorsWhat is used for acute treatment of gout (2 drugs)? How does each work?CochicineInhibits release of chemotactic and inflammatory mediators, inhibiting neutrophil activation. (highly toxic with low therapeutic index)IndomethacinDrug of choice to reduce inflammation. Why indomethacin?Others will inhibit uric acid excretionWhat drugs are used to prevent gout?Urocusuric agents prevent renal tubular reabsorption of urateProbenecid and sulfinpyrazoneThese drugs are not for patiets who already produce and excrete large amounts or urateKeep urine volume high and pH > 6AllopurinolInhibits xanthine oxidase, blocks urate synthesisGI irritation and skin reactions
43Management of Acetominophen overdose Dr. Laura James
44What is the most studied drug in toxicology? What is the major cause of acute liver failure in the United States today?Acetominophen toxicity (roughly 50% in 2003)Acetominophen is also one of the most common causes of pharmaceutical product poisoningWhat is the most studied drug in toxicology?AcetominophenHow long does absorption take of a therapeutic dose? Of an overdose?A therapeutic dose is completely absorbed within 1 hour, but overdose can delay absorption up to 4 hoursWhat order kinetics does acetominophen follow? What is the half life?It follows first order kinetics (exception in liver failure, 0 order kinetics)2.5 to 4 hours
45What is the mechanism of acetominophen? Mechanism is somewhat unknown, some recent evidence indicates a role in the central serotonin system.It is a weak inhibitor of cyclooxygenase, and as minimal antiinflammatory and neutrophil activation effects.What is good about acetominophen from a side effect stand point?It is not a gastric irritant and has no effect on plateletsWhat is the mechanism of acetominophen toxicity?Metabolism causes toxcity, (toxification by the liver)Describe the metabolism of acetominophenAt therapuetic doses >90 % undergoes glucuronidation and sulfation and is eliminated by the kidneysSmall remainder is metabolized by CYP P450 to NAPQI, a toxic metabolite. NAPQI is then detoxified by glutathione in non-overdose situations.CYP 2E1 is the primary P450 system involved.
46Agewise, who is more susceptible to acetominophen poisoning? Describe metabolism of Ac in overdose and the mechanism of toxicity (4 steps).Normal pathways are overwhelemed, build up of NAPQI occursGlutathione is depletedNAPQI binds to proteins (hepatocytes), forming adducts.Cell deathAgewise, who is more susceptible to acetominophen poisoning?Adults are more susceptible to acetominophen toxicity, whereas kids seem to be “relatively protected”How does ethanol increase the risk of acetominophen toxicity?Long term use of ethanol induces CYP 2E1 by 2-3 foldBinge use of alcohol at the time of overdose may decrease NAPQI formationWhat is a toxic dose of acetominophen in a child? In an adult? Is this information on the test?150 mg/kg7.5 gramsMax Therapeutic dose is 90 mg/kg/day in a child or 4 grams per day for adultyes
47Describe the four phases of acetominophen toxicity. hoursNausea, vomiting, elevation of hepatic transaminases, or asymptomatic24-72 hoursAbdominal tenderness in RUQ. Elevated hepatic enzymes. Clotting factors impaired. May have renal involvement.72-96 hoursSequelae of hepatic injury: jaundice, coagulation defects, hepatic encephalopathy, renal failure, death will happen in this phaseHard to get history at this point. If you show up to the hospital now, it is hard to treat you.4-14 daysThey get better and the liver fully recovers
48TreatmentWhat kind of liver damage is done by acetominophen toxicity (a path. term)?Centrilobular necrosisDescribe the treatment of acetominophen poisoning. Why is it important to treat quickly? What is the major adverse effect of this drug?N-acetylcysteine (NAC)Works at the glutathione step as a glutathione substitute to prevent “adduct” formationIV NAC got approved in 2004Efficacy is highly dependent on the time of NAC relative to the overdose.Treatment within 10 hours –6% risk of toxicity10-24 hours after overdose—26.4% risk of toxicityVomiting is the major side effect. Anaphylaxis is also a possibility, especially with IV dosing.What treatments can be effective if administered within two hours of the overdose?Activated charcoalDo you treat the patients nausea and vomiting?yes
49What is the maximum dose of acetominophen for adults? For children? 4 grams/day adults or 90mg/kg/day in childrenWhat percentage of acetominophen related acute liver failure is caused by opiod/acetominophen mixes?50 %Should you remember the numbers from this lecture?Oh yeah, big time. And remember/be able to use that graph.
50Opioid analgesics and antagonists Paul L. Prather—Feb 05, 2008
51What is the difference between an opioid and an opiate? Opioid is a general term for drugs that act at opioid receptors, whereas opiates are drugs that are derived from opium.What is the mechanism of the opioid receptors?These receptors hyperpolarize neurons which causes analgesiaThey open K channels to hyperpolarize the cell, and some close Ca channelsThey are G protein coupled receptors
52Describe the three receptor types. Mu receptors 99% of opioids act at this receptorCause supraspinal analgesia, miosis, respiratory depression, euphoria, dependenceDeltaLess well defined, also produces supraspinal and spinal analgesia, possibly less dependenceSometimes agonists cause seizureKappaSpinal and some supraspinal analgesia. Weak miosis, sedation, some respiratory depression, dysphoria
53ReceptorologyWhat receptors have the highest affinity for beta-endorphins?These endogenous opioids have the highest affinity for mu and delta receptors.What receptor do enkephalins have the most affinity for?Delta receptorsWhat about dynorphinsKappa receptorsAre mu receptor agonists better for dull pain or sharp pain?Mu agonists are better for dull painWhat are the three useful effects of exogenous opiate drugs?Activated mu receptors cause analgesia, both increasing the threshold to pain and decreasing the response to pain (the latter being more important)GI tract: increase tone and decrease motility due to mu receptor activationGreat for anti-diarrheal but causes constipation in chronic pain patientsAntitussive Effects: suppression of cough
54What bad things happen acutely after one takes opioids? Respiratory brain stem center depressionDecreased response to carbon dioxide, decreased automaticityCauses death in overdoseMiosisStimulation of edinger-westphal nucleus of 3rd cranial nerve. Little tolerance develops to pinpoint pupils.Sedation and EuphoriaNot mutually exclusive. Sedation may progress to sleep and coma, while euphoria plays a role in reinforcement and addictionEmesisDirect stimulation of mu receptors in the chemoreceptor trigger zone. Also potentiate vestibular stimulation.CardiovascularRelease of histamine may result in mild hypotension.Urinary retentionInhibition of urinary voiding reflex (tolerance develops)Biliary spasmChest wall rigidityWhat receptor is responsible for most of the toxicities listed above?The Mu receptor
55Tolerance and Dependence Define tolerance. Describe the clinical tolerance expected with opiate administration. Which 2 effects do not develop tolerance?Higher dose is required to produce an equivalent effect.Tolerance to opioids occurs to some effects but not others. More tolerance occurs to depressant than stimulant effects, and can cause 1000 fold dose-effect curve shiftage.Miosis and constipation (I think?)Describe opioid dependence.Dependence is produced by repeated opiod exposure that manifests in a withdrawal syndrome when chronic exposure is abruptly discontinued.Both tolerance and dependence probaby result from upregulation of the cAMP signal transduction pathway.What are the two types of dependence? Describe withdrawal in regard to opioids.Behavioral dependencePhysical dependenceWithdrawal begins 6 hours after last dose, peaks at 48 hours, declines for 10 daysSweating, nausea, vomiting, ccramps, shivering, shakes, restlessness.Not life threatening, reversible in any stage
56Chemistry What is the dependence mechanism? cAMP upregulation is a compensitory mechanism in chronic opioid administration.What is the prototype mu agonist? How can you turn morphine into heroin? Into Naloxone? How can you increase potency? Increase kappa effects?MorphineAcetylation at 3- and 6 increases potency and creates heroinAllyl substitutions at the N position (position 17) produces antagonists (naloxone)Stabilizing the C ring can greatly increase potencyLoss of C ring increases kappa effectsWhich form of opioids are active?The Levo forms are activeThe dextro forms are much less active (hence dextromethorphan as OTC cough medicine)
57Describe the pharmacokinetics of morphine? Describe heroin It has poor oral absorption and large first pass effect hour half life.Describe heroinIs 5-10 times more potent than morphineIt has greater lipid solubility than morphineIt has a very short (½ hour) half lifeShorter half life equals worse withdrawal symptomsDescribe codeine.Orally effective (60% oral bioavailability)2-4 hour half lifeWhat is different about meperidine (demerol)?It is less potent than morphine and has a shorter half life, and has significant anticholinergic effects (dry mouth, mydriasis)Meperidine has an active metabolite (normeperidine) that is excitatory and works at non-opioid receptors.
58How potent are fentanyl and congeners? What is their onset time? These are very potent ( x more potent than morphine) and very short acting.Their onset is between 5 and 15 minutes.Great for rigging horse races.Why is methadone good for addicts?Used for maintenance therapy for opioid addicts due to oral activity and long duration of action.What is propoxyphene (Darvocet)?It is the only opioid with a dextro active form (ON TEST)Is used orally and is less potent than morphine
59A Mixed Agonist/Antagonist and a Partial Agonist What is Pentazocine? For what and mixed with what is it used?Partial agonist/antagonist at Mu receptors, as well as analgesic activity at Kappa receptorsOften combined with naloxone for addictsWhat is buprenorphine used for? What is its mechanism?Is sometimes used as a step down from methadone therapy in addicts.It is also an effective analgesic in non-addictsIt is a partial agonist at mu receptors and antagonist at kappa receptors
60Naloxone Why is naloxone a good drug for opioid toxicity? It is a pure mu antagonist with a very high affinity for mu receptors (displaces opioids). Causes instant reversal of opioid overdose.What is even better about Naltrexone?Naltrexone is useful because it has a much longer duration of action. Recently used for alcoholism.What is unique about oxycodone?It is a controlled release analgesic with much publicity on abuse potential.
62Pain!What is pain?An unpleasant sensory or emotional experience associated with actual or potential tissue damage, or described in terms of such damage. It is complex, multidimensional phenomenon that is sensory, perceptual, and subjective in nature.Pain is usually considered a symptom but is rarely directly treatedWhat makes pain “chronic”? What are the two categories of chronic pain?Chronic pain lasts beyond the time that normal healing occurs (typically 3-6 months)Maglignant chronic painNon-malignant chronic pain (benign pain, 1/3 of americans)Includes headaches, low-back pain, arthritis, and others
63Pain Types What type of pain is the most difficult to treat? Non-malignant chronic painWhat are the types of non-malignant chronic pain?Nociceptive pain- responds well to opioidsSomatic- intense and discrete, well localized, often aching or throbbing.Visceral- diffuse, episodic, and poorly localized. This pain involves the internal organs and is propagated by sympathetic fibers.NeuropathicPain produced by the alteration of neurological structure and function. Different from nociceptive pain in that there is an absence of continuous nociceptive input. Frequently has a burning, lancinating, or electric shock quality, and persistent Allodynia.It does respond to opioids, but not as well as nociceptive pain
64Treatment Approaches What are the “conservative” treatments of pain? NSAIDS or COX-2 inhibitors, muscle relaxants, membrane stabilizers, TCA/AnticonvulsantsWhat are the other treatments of pain?Physical therapy, interventional therapy, or opioidsWhat makes methodone the best pain killer?It is both a mu agonist and a minor NMDA antagonistWhy is tramadol considered an opioid?While it has other functions, it is also a weak mu receptor agonist.How can you decrease pain in patients who are refractory to potent parenteral opioids?Either intrathecal opioids or nerve destruction
65Toxicity and Addiction What organ toxicities are common with long term opioid therapy?None, actually safer in this respect than NSAIDsMay cause some impairment of immune function, but the clinical importance of this is minimalWhat two effects do not get tolerance in long term opioid therapy?miosis and decreased gastric motilityWhat is addiction?A behavioral pattern characterized by overwhelming involvement with the use of a drug, the securing of the supply, and the high tendancy to relapseMost scientists say it is incurable/permanentWhat is the prevalence of addiction?19% in chronic pain patient, 16% of general public
66Dependence What is physcial dependence? The potential for an abstinence syndrome, or withdrawal following abrupt dose reduction, discontinuation, or administration of an antagonist.Is there a hypothesis that tolerance develops due to continuous stimulation of the NMDA receptor?Yes, again this is why methodone does not develop tolerance very oftenHow does one manage tolerance?Start with a differential diagnosis and ruling out any new problem that is causing painNext you can increase the dose or use an alternative opioid at a reduced doseOr you can use alternative pain management stratagies (drug holidays combined with other drugs)What is pseudoaddiction?Refers to the perception by observers of drug-seeking behavior in patients who have severe pain and are undermedicated or who have not received other effective pain treatment interventionsLooks like drug-seeking, but different in that when higher doses are provided and pain is effectively treated, these behaviors disappear
67How is the maximum dose of opioids determined? Keep going up until pain is effectively treated or side effects are limitingWhat is the financial problems with opioids?All opioids have a street value, 2.6 million americans report using analgesics for non-medical reasonsHow might one treat “complex regional pain syndrome” of the upper extremity?Stellate ganglion and lumbar sympathetic block
68Interventional crap What are the following indicated for? Celiac blockAcute and chronic pancreatitis, pancreatic carcinoma, upper abdominal malignanciesLumbar sympatheticComplex regional pain syndromes of the lower extremity, vascular insufficiencySuperior hypogastricMid-gut and colon malingnancies, sometimes rectal and pelvic malignanciesFor all of those other interventional therapies on page 102 of the syllabus, my suggestion is just guess based on where in the body is affected (e.g. cervical epidural steroid injection for cervical radiculopathy). If you want to memorize it, have fun with that.
69Atypical deliveryWhy is neuraxial drug delivery sometimes preferable? When is it indicated?It can be effective for multiple pains, is nondestructive, requires lower doses with lower side effectsWhen maximal medical therapy has failed in the treatment of chronic pain with known pathophysiology that is sensitive to the infused agent. It helps if the patient/family have realistic expectationsWhat is the most used local anesthetic for intrathecal pain management?BupivacaineWhat adrenergic agent if especially useful in intrathecal use?Clonidine (FDA approved for pain)What muscle relaxant is good for cerebral palsy? What is the new FDA approved drug for intrathecal pain?BaclofenziconotideThere is way more information on pages , but I’m probably not learning it.
70Nicotine and Other stimulants Dr. Owens, Feb 05, 2008
71Stimulants of abuseWhat are the two main forms of abused cocaine? Describe each.Cocaine hydrochlorideCan be sniffed as a “line” or “shot” ivSniffing can make your nose rot off (vasoconstrictor)Cocaine free baseCrack or rock cocaine, which is volatilized for inhalation. Onset is even fasterWho developed free-basing?The tobacco industry developed it to serve their purposes. They were hanging out with Hitler and Genghis Kahn a lot at the time.What makes cocaine/methamphetamine so addictive?These drugs kidnap people’s reward centers. Many addiction scientist relate it to the experience of an orgasm.Describe the pharmacological actions of cocaine.Initially, there is a very pleasurable “rush,” a feeling with sexual overtonesEuphoria, increased energy, increased sensory awareness, decreased need for sleep, anorexia, increased activityPost euphoria—Increased anxiety, suspicion of others, delusions, paranoiaIncreased heart rate, blood pressure, incidence of stroke
72Kinetics Describe a “run.” A person uses the drug until all available drug is consumed.What drugs are commonly combined with cocaine? Why?Alcohol, sedative hypnotics, opiates, marijuanaUsed to treat the side effects of the excess stimulation caused by cocaine.What is the half life of cocaine?45 minutesMost addicts like the initial rush and do not care for the next minutes of feeling.Describe the metabolism of cocaine. What metabolite is created when cocaine is used with alcohol?It is cleared at about 3000mL/min due to extrahepatic metabolism, this results in the very short half life. Urine metabolites (benzoylecognine) are detectable for 3-4 days.Cocaethylene is created when cocaine and alcohol are coadministered
73Tolerance and Dependence Describe cocaine tolerance.Minimal tolerance develops, and there is some evidence of sensitization to some effectDescribe the physical dependence to cocaine.There is little or no physical dependence, though cocaine produces one of the most powerful behavioral and physiological dependence of any drug of abuse.What is the pharmacologic mechanism of cocaine?Cocaine blocks the reuptake of released catecholamines and 5-hydroxytryptamine as well as dopamine reuptakeBlocking dopamine reuptake seems to be responsible for CNS effects and abuse potentialDescribe the acutely cocaine overdosed patient.The patient experiences paranoid aggression and cardiovascular crisis; he is dangerous.What are the new developments in the treatment and prevention of cocaine dependence?Cocaine antibodies to act as a pharmacokinetic antagonist
74Amphetamine What isomer of amphetamine is most addictive? d or (+) isomerWhy is methamphetamine so dangerous societally?It is the second most abused drug in the world and produces large amounts of violence and criminalityIs the rush different from the cocaine rush?The “rush” is almost identical, but lasts much longer.In what ways does methamphetamine affect neurotransmitter levels in the synapse?It causes the release of catechol amines and 5-HT. The CNS effects are thought to be mediated by dopamine whereas the CV effects are produced by NE.
75Crystal Describe tolerance and dependence with methamphetamine. Tolerance is greater than with cocaine, strong behavioral dependence is mixed with physical dependence.In what ways is treatment of meth intoxication different from treatment of cocaine intoxication?Treatment is more aggressive and more likely to require a benzo, alpha blocker, and/or an antipsychotic agent.What is kind of unique about methamphetamine regarding serotonin?Meth users have depleted serotonin neurons, neurotoxicity, and hyperstupidityDescribe the typical meth head.Patients often present as thin, hyperactive, paranoid, with CV effects, bruxism (teeth grinding), and ultra-bad teeth
76Smoking!!!! Hooray!!!!!What percentage of deaths are related to smoking? Cancer cases?20% of deaths are related to smoking, 20% of new cancers are related to smoking.What percentage of smokers die from smoking?1 of 2 smokers die from smokingDescribe the withdrawal syndrome from nicotine.Anxiety, irritability, restlessness, difficulty concentrating, hunger, weight gain, insomnia, dysphoriaSymptoms last 1-2 weeks, cravings can last much longer/indefinitelyWhat are the three main disease processes with smoking?Cancer, heart disease, and chronic lung diseaseOf the many toxic chemicals in cigarette smoke, which are the most potent carcinogens?Aromatic amines, nitrosamines, and polyaromatic hydrocarbons
77Smoking PathogenesisWhat is the chief metabolic product of nicotine? What molecule is a good indication of recent smoking?CotinineCarboxyhemoglobinDoes nicotine cause cancer?noWhat is the mechanism of smoking induced cardiovascular disease?Carbon monoxide decreases oxygen delivery to tissues. Nicotine activates sympathetic system (release of catechol amines) and causes glucose intolerance. Oxidant gases play a role.
78COPD and Quitting What is the mechanism of smoking-induced COPD? Irritant gases and cilotoxic agents produce structural abnormalities in cilia and impair clearance. Mucous glands become hyperplastic causing increased mucous and cough. Excess elastase activity destroys alveolar septa (producing emphysema).How effective is medication in helping people quit smoking?It is useful in motivated patients, particularly for the early withdrawal stage of quitting. Medication aproximately doubles the quit rate achievable with counseling alone.
79CNS Stimulants: Theapuetic Uses and Toxicity February 07, 2008Galen R. Wenger
80Chemical Convulsants What are the chemical convulsants? Strychnine (common AR rodenticide), picrotoxin, and pentylenetetrazolWhat is the mechanism of stychnine? Of picrotoxin and pentylenetetrazol?Blocks postsynaptic inhibition of glycine in the spinal cord.Picro and penty block presynaptic inhibition produced by GABA in all areas of the brain and probably bind to a site within the pore of the GABAA receptor.For what were chemical convulsants previously used?Stimulation of respiration in treatment of depressant overdose. This treatment was great at increasing death rates, if you’re into that.What is pentylenetetrazol currently used for?Diagnosis of seizure disordes (fun!)
81Strychnine poisoningWhat kind of seizure does strychnine poisoning cause?Opisthotonic seizure (shown to the right)How are these seizures and strychnine poisoning treated?IV diazepam, dark quiet room, activated charcoal if drug is still in GI tract.
82Methylxanthines What are the two methylxanthines (that we covered)? Caffeine and theophylline (both are present in tea, by the way)What are the CNS effects of mg of caffeine? The cardiovascular system? The musculature?Stimulation of CNS and medullary respiratory centers.Decrease in rate at low dose, tachycardia and increased CO at higher doseConstricts the vasculature of the CNSIncreased capacity for work with performance enhancing effectsHow does caffeine increase urine output?The mechanism is unclear, increased CO with some change in kidney function (urine composition similar to thiazide diuretic use)
83Mechanism and Kinetics What is the currently accepted mechanism of methylxanthines?Antagonism of adenosine is probably responsible for most of these drugs’ effects.Translocation of Ca++, inhibition of phosphodiesterase (with increased cAMP) also occur in vitro, but may not be important clinically.What is the half life of methylxanthines? What percentage is metabolized before excretion?3-7 hours in adults (Caffeine)Half life is variable: long in liver diseased pregnant women on contraceptive pills, short in smokers taking phenytoin and barbiturates (yes I know that pregnant women don’t usually take contraceptive pills)>90%
84Toxicity and Dependence What toxicities are noticed with high doses of methylxanthines?Nervousness, insomnia, delirium, convulsions (not usually fatal)Is caffeine mutagenic or teratogenic?Maybe, it does cause little mutated plant babies.Copout answer—“advise pregnant women to use caution and moderation”Define physical dependence (again).Upon abrupt discontinuation of a drug, physical withdrawal symptoms occur.
85AmphetaminesWhat are the amphetamine class psychomotor stimulants (4)?Amphetamine, methamphetamine, methylphenidate, phentermineWhat effects do these drugs have in the periphery?At low doses, methamphetamine has no peripheral effects.Others do.Rank their potency in the CNS.Methamphetamine > d-amphetamine > L-amphetamine & methylphenidateWhat are the primary CNS effects of amphetamines?Stimulate medullary respiratory center, increase motor activity, elevate mood, insomnia, decrease fatigue
86Mechanism and Use What is the mechanism of amphetamines? Major mechanism is probably a release of NE (periphery), dopamine, and maybe serotonin from nerve endings. There is also an inhibition of reuptake of transmitter by nerve endings as well as a possible small direct action on catecholamine receptors.What is the now abandoned therapeutic use of amphetamines?Weight control by effect on appetite (lasts about two weeks)Now considered unethicalWhat are the current uses of amphetamines?Attention Deficit Hyperactivity DisorderHyperkinetic syndrome / ADHD, a paradoxical effectMethylphenidate and d-amphetamine have similar efficacyNarcolepsy
87Tolerance and Toxicity Describe the physical dependence and withdrawal experienced with amphetamines.The dependence is called “withdrawal of the amphetamine type” and is basically the opposite of the amphetamine effects (eat a lot, sleep a lot)What are the adverse effects of amphetamines in children? What toxicities occur?In children, insomnia, abdominal pain, anorexia, weight loss,Following high doses of amphetamines, a psuedo-psychotic syndrome develops:Visual hallucinations predominante with some auditory hallucinations, paranoid thoughts, changes in affect, prounounced sympathetic effects.
89Ethanol basics Is ethanol a unique drug? In what ways (3)? Why yes it is, thanks for asking.It is the only drug metabolized to yield energy, about 7Kcal per gram. Huge doses are administered, and it is the only drug in western society in which self-induced intoxication is legally acceptable and socially ultra-cool.What kind of doses are needed to produce CNS effects?Humongenormous doses, around 1-3 grams/kgMinimal effect in man below 15 gramsHow many chronic alcoholics are there in the U.S.?About 10 million, (used recreationally by 2/3 of U.S. population)What is the mechanism of absorption of ethanol?Passive diffusion in the stomach, small intestine, and colon. It will occur up to a concentration of about 50%, at higher concentrations (funneling everclear) it directly damages the GI system.Can the lungs absorb ethanol?Ethanol vapor is rapidly absorbed from the lungIn what body compartemnt is ethanol distributed?Ethanol is distributed into total body water and is absorbed into organs and tissues based on their blood supply.
90Kinetics How is expired air used to measure blood alcohol content? Ethanol in 2100mL of expired air is equal to ethanol present in 1mL of blood at a wide range of concentrationsHow is mg% related to g/dL100 mg% = 0.1 g/dLWhat are the two routes of ethanol metabolismAlcohol dehydrogenase (90%) and P450 system (10%)What is the rate limiting step in ethanol metabolism?Conversion of ethanol to acetaldehyde by alcohol dehydrogenase (the first step) is rate limiting and typically saturated.Both steps use NAD and result in NADH productionWhat order kinetics does ethanol metabolism follow?Due to saturation of alcohol dehydrogenase, 0 order7-10 grams of ethanol per hour is metabolizedWhat is the maximum amount of calories absorbed from alcohol per day?calories per day
91Tolerance, Mechanism, Mellanby See sylabus for dose dependent effects.What is the legal level of alcohol in blood in most states (including arkansas)?0.08 g/dLWhat is the mechanism of action of ethanol?Not fully understood, there is an interaction with protein structures affecting neuronal excitability. Many ion channels are also affected, including GABA, nicotinic, and glutamate receptors.Replaces water in protein cavities which affects protein structureWhat is the maximum tolerance to alcohol observed? What is responsible for the drug dispositional tolerance?About two fold, which is a minimal tolerance compared with other drugs (e.g. marijuana 1000x tolerance has been observed)Induction of microsomal P450 system (as well as a pharmacodynamic tolerance)Is alcohol cross-tolerant to other CNS depressants?YesWhat is the Mellanby effect?People seem to be behaviorally drunk at about .08 g/dL on the ascending (becoming drunk) end of the curve, but they sober up at higher levels on the down slope (after discontinuation)
92Withdrawal of ethanol Does physical dependence occur? Describe it. Yes, it’s a two part withdrawal syndromePeak effects occur at hours, withdrawal lasts 5-7 days. Withdrawal occurs in two phases:Phase 1-Hyperirritability, exaggerated reflexes, sleeplessness, tremor, muscular tension, cold sweaty skin, nausea, thirstPhase 2- (Delirium Tremens)Severe hyperactivity with delirium, hallucinations, fever, profuse sweating, intense vasodilation, severe tachycardia, tonic-clonic seizures
93Adverse Effects What are the two ways to treat withdrawal? Either slowly reduce the ethanol dose, or switch to another CNS depressant and slowly lower that dose (usually benzos)What are the (adverse) effects of ethanol on the liver? The GI tract? The endocrine system? The kidney?Induction of P450, fatty degeneration of the liver, can lead to cirrhosisErosive gastritisGynecomastia, testicular atrophy, interference with release of prolactin, growth hormone, and antidiuretic hormoneDecreased release of ADH with increased fluid intake
94ToxicityWhy don’t people usually drink enough ethanol to kill themselves?They usually lapse into a “coma” before they are able to drink enough ethanol to kill themselvesWhat emergent condition can be misdiagnosed as ethanol intoxication?Diabetic comaEthanol on breath does not make the diagnosis!How can one treat alcohol overdose?Enhance elimination with gastric lavage or hemodialysisSupportive care: keep him breathing and perfusing tissues, correct metabolic acidosis, decrease intracranial pressure (mannitol), prevent aspiration of vomitus.What percent of chronic alcoholics have liver damage? Cirrhosis?100%20%
95Chronic Alcoholism How do you treat wernicke korsakoff? High dose thiamineHow common is fetal alcohol syndrome? What are its three primary features for diagnosis? How much maternal consumption of ethanol is needed for “definite risk”?4-7 per 1,000 live births in U.S.Microcephaly, prenatal growth deficiency, short palpebral fissuresDefinite risk with intake above 3/oz per dayWhat are the treatments of chronic alcohoism?Pharmacologic- disulfiram, naltrexone, SSRIs12 step program
96Disulfiram Who is disulfiram good for? How does it work? Highly motivated patientsIt inhibits aldehyde dehydrogenase, increasing levels of acetaldehyde (aldehyde syndrome created)Feels like a myocardial infarctionWhat are the uses of ethanol?It is used as a solvent for many other drugs, to cool the skin (alcohol baths), as a sedative, and as a “head-cold” remedy
97Wood AlcoholWhat are the initial symptoms of methanol? What are the toxic symptoms? What is the cause of death in overdose?A mild drunk: euphoria, muscle weakness, disinhibitinWithin 3-36 hours, a series of toxic symptoms including: N/V, headache, delirium, GI pain, back pain, cold clammy hands, hyperemic optic disks.Severe cases include a metabolic acidosis with an anion gap, fixed dilated pupils, retinal damage, bradycardia, coma, seizuresImmediate cause of death is respiratory arrestWhat is responsible for the toxicity of methanol?The metabolism of methanol is to formaldehyde and formic acid. These metabolites produce toxicity and acidosisHow do you treat methanol poisoning?Maintain airway, infusion sodium bicarbonate, administer large doses of ethanol (use up the aldehyde dehydrogenase)Can use hemodialysis, emesis.
98Cannabinoids and Hallucinogens W.D. WessingerFebruary 11, 2008
99Marijuana What is marijuana? What is Hashish? Dried parts of the cannabis plant, usually leaves and flower heads that are used as a smoking mixtureDried resinous exudates of the flowering topsWhat is the most abundant psychoactive agent in marijuana?Delta-9-tetrahydrocannabinal, which makes up % of the weight of marijuana.Describe the effects of marijuana.Euphoria, altered perceptions, impaired short term memory, impaired balance, decreased concentration/attention, 4-8 hour impairment post-euphoria.
100Pharmacology of Marijuana What effects does marijuana have on the cardiovascular system?Increases of bpm, pulse of 140 bpm can occur.Increased blood pressure while lying down but decreased while standing.Vasodilation of scleral and conjunctival vessels resuting in blood shot eyes.What neurological effects occur with high doses of marijuana?Frank hallucinations, anxiety and panic replace euphoria, delusions, paranoid feelingsDescribe cannabinoid CB1 receptors. CB2 receptors.These G-protein coupled receptors are widely distributed throughout the CNS, especially in the cortex, hippocampus, mesolimbic area, cerebellum, medulla, and substantia nigra.CB2 receptors are found in the periphery, mostly associated with immune tissuesWhat is the endogenous ligand for these receptors?Anandamide, an arachidonic acid derivative
101Tolerance and Legality What are the long term problems with marijuana use?Memory and learning problems, anxiety and panic attacks, loss of judgment, drug testing, and jail.Dramatic tolerance is noted to all but which effects?Cardiovascular effectsIs marijuana legal in medical settings? Explain.Marijuana is classified as a chedule I drug (with no recognized medical value and a high abuse potential), but synthetic THC is a schedule II drug that is FDA approved for a few indications. They are:Anti emetic for cancer chemotherapyAppetite stimulant in AIDS wasting syndromeOther proposed uses include anticonvulsant, muscle spasm and decreasing intraocular pressure.
102Lysergic acid diethylamide Describe LSD (chemically).Lysergic acid diethylamide is an ergot alkaloid derived semi-synthetically from the fungus Claviceps purpurea that grows on grains such as wheat and rye.Chemically it is an indolealkylamine that is structurally similar to NE, dopamine and serotonin.How much LSD is required to produce an effect?20-25 micrograms can produce an effect.What is the most noteworthy effect produced by LSD?Visual hallucinations that are elaborated from visual disturbances such as prolonged afterimages and an overlapping of present and past perceptions.Auditory hallucinations are rareWhat are the other effects of LSD?Increased blood pressure, dilated pupils, piloerection, hyperreflexia, pyrexiaWhat is the mechanism of LSD?Probably an agonist at 5-HT2, though it probably also affects many other receptorsGive the five dollar word for flashbacks?Hallucinogen persisting perception disorderCan LSD precipitate serious depression or prolonged shizophrenic episodes?yes
103LSD Does tolerance occur with LSD? Does dependence occur with LSD? Yes, it appears rapidly and goes away rapidly.Cross-tolerance to other hallucinogens like beta phenylethylamines and psilocybin.Does dependence occur with LSD?NoWhat is LSD used for medically?LSD is a schedule I drug with no recognized medical uses.
104Peyote and X What is MDMA? What is MDA? What are its effects? MethyleneDioxyMethAmphetamine, or ecstacy, is a beta phenylethylamine hallucinogen. It is the newest in this class and is the successor to MDA.What is MDA? What are its effects?3,4-methylenedioxyamphetamine is also known as mescaline and is the active component of the peyote cactus.It is a mild intoxicant producing euphoria without frank hallucinationsWhat medical use did MDMA have in the 1970s?Psychotherapists used MDMA in the 70s to help patients talk about their feelings. Then they played techno music put glow-sticks in their mouths.
105MDMA toxicityWhat is it called when MDMA users take additional doses every couple of hours?StackingWhat effects does MDMA have?Mild hallucinogen and stimulant, euphoria, clarity of emotions and feeling of well being, hypersensitivity to touch, bruxism, increased body temperatureWhat are the symptoms of MDMA toxicity?Increased pulse and BP, heat exhaustion, brain damage/neurotoxicity (decreased serotenergic functioning)How much ecstacy is required to produce serotenergic damage?One dose is plenty to decrease serotenergic function. Cognitive deficits occur.Is it a good idea to use phenothiazines for phenylethylamine overdose? What is a better choice?Probably not because some people have died, probably due to the anticholinergic interaction with the sympathomimetic effect.Benzodiazepines seem to be effective and are less dangerous
106Dissociative Anesthetics What is the prototype dissociative anesthetic? What are the other dissociative anesthetics?Phencyclidine (PCP). I love its other names: angel dust, KW, rocket fuel, embalming fluid.Phencyclidine, ketamine, and (I guess) dextromethorphan.Was phencyclidine ever used as a general animal anesthetic? What is phencyclidine’s schedule?NoSchedule II, though analogs and precursors are schedule I.What is Sherm’s?A street drug consisting of marijuana cigarettes impregnanted with phencyclidine (“dipped in embalming fluid”)
107Special K and Cough Syrup What is ketamine used for medically? What schedule is ketamine?Pediatrics, burn patients, and in veterinary medicineSchedule IIWhat schedule is dextromethorphan? Where is it found?It is not a schedule drug and is available OTC in cold and cough preps as an anti-tussive.What is the mechanism of the dissociative anesthetics?They all work by non-competitively antagonizing NMDA receptors, binding to the NMDA receptor complex in the ion channel, blocking it.Which dissociative anesthetic is the most potent?Phencyclidine is the most potent and long lasting (6-10 hours)
108Effects, Dependence, Overdose What are the effects of dissociative anesthetics?Euphoria/dysphoria, analgesia (reported as superhuman strength), motor incoordination, drunken ataxia, slurred speech, vertical nystagmusHallucinations of both visual and auditory types: distortions of space, time, and body image, detachment from environment, dissociation (“out-of-body”)Do tolerance or dependence occur with PCP?Yes, both have been noted in animals, including withdrawal syndromes.What psychiatric (mis)diagnosis is often given to abusers of PCP?SchizophreniaWhat are the symptoms of PCP overdose?Agitation alternating with stuporIncreased BP, psychosis, myoclonus, seizures, trauma?, rhabdomyolysismyoglobinuriarenal failureMotor seizures and respiratory depression.
109Overdose How might one treat PCP overdose? Just give diazepam and wait, everything else (antipsychotics, urinary acidification, talking them down) is bad.And keep them from hurting themselves or others.