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Antipsychotic Agents: 1 st Generation. Early antipsychotics Name all of the prototype 1 st generation antipsychotic agents (7) Name all of the prototype.

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Presentation on theme: "Antipsychotic Agents: 1 st Generation. Early antipsychotics Name all of the prototype 1 st generation antipsychotic agents (7) Name all of the prototype."— Presentation transcript:

1 Antipsychotic Agents: 1 st Generation

2 Early antipsychotics Name all of the prototype 1 st generation antipsychotic agents (7) Name all of the prototype 1 st generation antipsychotic agents (7) Thioridazine, chlorpromazine, thiohixene, fluphenazine, loxapine, haloperidol, and molindone Thioridazine, chlorpromazine, thiohixene, fluphenazine, loxapine, haloperidol, and molindone Which one is the aliphatic derivative? The piperidine derivative? The piperazine derivative? Which one is the aliphatic derivative? The piperidine derivative? The piperazine derivative? Chlorpromazine Chlorpromazine Thioridazine Thioridazine Fluphenazine Fluphenazine Which one is the thioxanthene? The Butyrophenone? The dibenzoxazipine? The dihroindolone? Which one is the thioxanthene? The Butyrophenone? The dibenzoxazipine? The dihroindolone? Thiohixene Thiohixene Haloperidol Haloperidol Loxapine Loxapine molindone molindone

3 Indications and Effects What are the clinical indications of the 1 st generation “typical” antipsychotics? What are the clinical indications of the 1 st generation “typical” antipsychotics? Schizophrenic (or otherwise psychotic) patients, for antiemetic properties, and to stop hiccups Schizophrenic (or otherwise psychotic) patients, for antiemetic properties, and to stop hiccups Which of the typical antipsychotics are most effective? Which of the typical antipsychotics are most effective? They are all equally effective They are all equally effective Which are the most potent? The least potent? Which are the most potent? The least potent? The butyrophenones and piperazine derivatives are the most potent (haloperidol and fluphenazine) The butyrophenones and piperazine derivatives are the most potent (haloperidol and fluphenazine) The aliphatic and piperidines are the least potent (chlorpromazine and thioridazine) The aliphatic and piperidines are the least potent (chlorpromazine and thioridazine) What receptor mediates the activity of these compounds? What receptor mediates the activity of these compounds? Activity occurs through antagonism at the D2 dopamine receptor Activity occurs through antagonism at the D2 dopamine receptor How do these drugs prevent nausea and emesis? Which drug is NOT anti-emetic? How 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 zone The antiemetic properties of these drugs are mediated through blocking D2 receptors in the emesis chemoreceptor trigger zone Thioridazine has no significant anti-emetic activity Thioridazine has no significant anti-emetic activity

4 Groups Among this drug class, how is potency of the drug correlated with degree of extrapyramidal symptoms? Among 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 effects Higher potency seems to correspond with higher levels of extrapyramidal side effects What three other receptors are blocked by some of these drugs? What group (generally) has more of these effects? What three other receptors are blocked by some of these drugs? What group (generally) has more of these effects? Some of the 1 st generation antipsychotics are also effective blockers of alpha adrenergic receptors, muscarinic cholinergic receptors and histamine receptors. Some of the 1 st 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 sites In general the lower potency antipsychotics have greater activity at these other receptor sites Which drug (listed) is commonly used for intractable hiccups? Which drug (listed) is commonly used for intractable hiccups? chlorpromazine chlorpromazine

5 Mechanism 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? 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 activity Blocking dopamine receptors in the mesolimbic-mesocortical systems results in the antipsychotic activity Blocking dopamine receptors in the nigrostriatal system mediates the extrapyramidal effects Blocking dopamine receptors in the nigrostriatal system mediates the extrapyramidal effects Antipsychotic activity is mediated through which subtype of dopamine receptor? Antipsychotic activity is mediated through which subtype of dopamine receptor? The D2 subtype The D2 subtype Rate these drugs as a group on oral availability, first pass effect, protein binding, and lipid solubility. Rate 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 crappy Put simply, they have a lot of all of that except for oral availability, which is poor with incomplete absorption. They are pharmacokinetically crappy Which two groups have active metabolites? Which two groups have active metabolites? Aliphatics and piperidines (chlorpromazine and thioridazine) Aliphatics and piperidines (chlorpromazine and thioridazine)

6 Adverse Effects—Motor What motor adverse effect is common with the 1 st generation antipsychotics in the first 5 days? Describe the syndrome. How is it treated? What motor adverse effect is common with the 1 st generation antipsychotics in the first 5 days? Describe the syndrome. How is it treated? Acute dystonia Acute dystonia Spasms of face, neck, and back Spasms of face, neck, and back Treated with anticholinergics Treated with anticholinergics What motor adverse effect is common with the 1 st generation antipsychotics between days 5 and 60? Describe the syndrome. How is it treated? What motor adverse effect is common with the 1 st generation antipsychotics between days 5 and 60? Describe the syndrome. How is it treated? Akathisia Akathisia is 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/Akathisia is 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/Akathisiahttp://en.wikipedia.org/wiki/Akathisia Treat by lowering the dose and/or administering anticholinergics Treat by lowering the dose and/or administering anticholinergics What motor adverse effect is common with the 1 st generation antipsychotics between days 5 and 30? Describe the syndrome. How is it treated? What motor adverse effect is common with the 1 st generation antipsychotics between days 5 and 30? Describe the syndrome. How is it treated? (drug induced) parkinsonism (drug induced) parkinsonism Looks like parkinson’s disease Looks like parkinson’s disease Treat by lowering the dose and/or administering anticholinergics Treat by lowering the dose and/or administering anticholinergics

7 Even more side effects Describe the perioral tremor and its treatment. 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 anticholinergics 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 anticholinergics The secretion of which hormone is increased by 1 st generation antipsychotics? Which two hormones are decreased? The secretion of which hormone is increased by 1 st generation antipsychotics? Which two hormones are decreased? Hyperprolactinemia occurs with these drugs Hyperprolactinemia occurs with these drugs Decreased gonadotropin and estrogen release Decreased gonadotropin and estrogen release

8 Do first generation antipsychotics cause edema or weight gain? Do first generation antipsychotics cause edema or weight gain? Yes, both Yes, both Which anti-psychotics (potency) cause more sedation? Which anti-psychotics (potency) cause more sedation? The lower potency anti-psychotics cause more sedation The lower potency anti-psychotics cause more sedation Which 1 st generation antipsychotic is best to use in a patient with a history of seizures? Which 1 st 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. 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? 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. 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% Mortality is >10% Treatment includes discontinuing the antipsychotic and adminstering dantrolene, along with supportive care Treatment includes discontinuing the antipsychotic and adminstering dantrolene, along with supportive care Way more side effects

9 More bad stuff Which autonomic receptors are commonly blocked by antipsychotics? Which 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. 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? 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. They cause both a blue-gray skin discoleration and a photosenitivity that resembles a severe sunburn. Name three drug interactions of 1 st generation antipsychotics. Name three drug interactions of 1 st generation antipsychotics. They potentiate the effect of CNS depressants, opioids, and antihistamines They potentiate the effect of CNS depressants, opioids, and antihistamines They reduce the effectiveness of L-dopa in patients with parkinsonism (antagonism) They reduce the effectiveness of L-dopa in patients with parkinsonism (antagonism) They have additive anticholinergic effects with tricyclic antidepressants They have additive anticholinergic effects with tricyclic antidepressants How does a physician choose between the various antipsychotics in determining which drug to give a patient? How 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 The selection of an agent often depends upon the side effects and the ability of the individual patient to tolerate them

10 Atypical 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.”

11 Clozapine For which patients is clozapine approved? For which patients is clozapine approved? Clozapine is only approved in patients suffering from schizophrenia who are refractory to more traditional antipsychotics. Clozapine is only approved in patients suffering from schizophrenia who are refractory to more traditional antipsychotics. How potent is clozapine? How potent is clozapine? 2x potent as chlorpromazine, (low potency) 2x potent as chlorpromazine, (low potency) What makes clozapine’s side effect profile superior to other antipsychotics? What pharmacologic difference might account for this? 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 hyperprolacinemia Clozapine does not produce severe extrapyramidal dysfunction nor hyperprolacinemia Clozapine has a relatively low affinity for D1 and D2 receptors and is more specific for D4 Clozapine has a relatively low affinity for D1 and D2 receptors and is more specific for D4 Also, chronic treatment does not result in an increase in the number or sensitivity of dopamine receptors Also, chronic treatment does not result in an increase in the number or sensitivity of dopamine receptors What non-dopamine systems are affected by clozapine? What 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. Clozapine causes changes in alpha adrenergic and muscarinic receptors, as well as blocking serotonin (5HT-2 rec) receptors.

12 Just a few side effects What is the half life of clozapine? Which patients get higher plasma levels? What is the half life of clozapine? Which patients get higher plasma levels? Half life is 12 hours Half life is 12 hours Young, women who smoke get higher plasma levels than older, non-smoking men. Young, 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? 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. Sedation, fatigue, weight gain, and diabetes are common. Nausea and vomiting may limit the dose. Nausea and vomiting may limit the dose. Clozapine also causes excess salivation and severe drooling on your pillow at night time. Clozapine also causes excess salivation and severe drooling on your pillow at night time. Potentially fatal agranulocytosis (1-2%, requires frequent blood tests) Potentially fatal agranulocytosis (1-2%, requires frequent blood tests) What percentage of patients on clozapine develop new onset seizures? What percentage of patients on clozapine develop new onset seizures? 2-5% 2-5% For what patients is clozapine contraindicated? 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) Any patients with any kind of bone marrow problem or leukopenia, or who are taking anything else that may affect the bone marrow (carbamazepine)

13 The other atypicals Name the four mixed antagonist atypical (2 nd Generation) anti-psychotics. Name the four mixed antagonist atypical (2 nd Generation) anti-psychotics. risperidone (risperdal), olanzapine (zyprexa), quetiapine (seroquel), and ziprasidone (zeldox) risperidone (risperdal), olanzapine (zyprexa), quetiapine (seroquel), and ziprasidone (zeldox) Brand names are listed parenthetically just because the BS people use them some of the time Brand names are listed parenthetically just because the BS people use them some of the time All of these drugs antagonize D2 dopamine receptors, but what else do each of these drugs do? What is the half life of each drug All of these drugs antagonize D2 dopamine receptors, but what else do each of these drugs do? What is the half life of each drug Risperidone Risperidone Binds D2, 5-HT2, alpha adrenergic and histaminic H1 Binds D2, 5-HT2, alpha adrenergic and histaminic H1 20 hours (w/active metabolie  paliperidone) 20 hours (w/active metabolie  paliperidone) Olanzapine Olanzapine 5-HT2, 5-HT3, 5-HT6, D1, D2, D4, H1, α-1, and muscarinic M1 5-HT2, 5-HT3, 5-HT6, D1, D2, D4, H1, α-1, and muscarinic M1 30 hours 30 hours Quetiapine Quetiapine Has a higher affinity for 5-HT2 than D2 Has a higher affinity for 5-HT2 than D2 6 hours 6 hours Ziprasidone Ziprasidone D2, 5-HT2, H1 D2, 5-HT2, H1 7 hours 7 hours How are these drugs absorbed orally? How are these drugs absorbed orally? well well Which is the only of these drugs that has an active metabolite? Which is the only of these drugs that has an active metabolite? Risperidone (paliperidone) Risperidone (paliperidone)

14 Side effects for days What are the most common side effects of risperidone? What are the initial side effects (elderly)? What are the most common side effects of risperidone? What are the initial side effects (elderly)? Asthenia, insomnia, difficulty concentrating Asthenia, insomnia, difficulty concentrating Asthenia Orthostatic hypotension and reflex tachycardia Orthostatic hypotension and reflex tachycardia Of the atypical antipsychotics, which has the highest incidence of extrapyramidal effects? Which causes the most hyperprolactinemia? Of the atypical antipsychotics, which has the highest incidence of extrapyramidal effects? Which causes the most hyperprolactinemia? Risperidone Risperidone What are the main side effects of olanzapine? What 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) 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? Which two atypical antipsychotics cause the most weight gain? Clozapine and olanzapine Clozapine and olanzapine What are the strange and different adverse effects of quetiapine? What are the strange and different adverse effects of quetiapine? Increased serum aminotransferase, cataracts (in dogs) 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? 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.) Ziprasidone (so don’t use it with other QT prolonging drugs or arrhythmia pts.) Of the atypical antipsychotics, ziprasidone causes the least weight gain. Of the atypical antipsychotics, ziprasidone causes the least weight gain.

15 Aripiprazole What drug causes marked decrease in the clearance of quetiapine? What drug causes marked decrease in the clearance of quetiapine? Phenytoin Phenytoin How do the newer drugs stack up against haloperidol? How do the newer drugs stack up against haloperidol? Risperidone and olanzapine have been shown to be at least as effective as haloperidol Risperidone and olanzapine have been shown to be at least as effective as haloperidol What is the prototype partial agonist antipsychotic? What is the prototype partial agonist antipsychotic? Aripiprazole Aripiprazole For what is aripiprazole useful? For what is aripiprazole useful? Equally useful as haloperidol for antipsychosis, aripiprazole is also useful in acute manic episodes Equally useful as haloperidol for antipsychosis, aripiprazole is also useful in acute manic episodes What is the mechanism of aripiprazole? What is the mechanism of aripiprazole? Partial agonist at D2 and 5-HT1a receptors and antagonist at 5-HT2a receptors Partial agonist at D2 and 5-HT1a receptors and antagonist at 5-HT2a receptors Is a “dopamine system stabilizer” in that it maintains a medium amount of D2 activation Is a “dopamine system stabilizer” in that it maintains a medium amount of D2 activation What is the half life of aripiprazole? In what patients can this be longer? What is the half life of aripiprazole? In what patients can this be longer? 75 hours 75 hours In patients with variation in the CYP 2D6 system, the half life can be 146 hrs. In patients with variation in the CYP 2D6 system, the half life can be 146 hrs.

16 More aripiprazole and conclusions What are the side effects of aripiprazole? What are the side effects of aripiprazole? Anxiety, headache, nauseas and vomiting, constipation, insomnia and somnolence, lightheadedness Anxiety, headache, nauseas and vomiting, constipation, insomnia and somnolence, lightheadedness No extrapyramidal effects, hyperprolactinemia, hyperlipidemia, hyperglycemia, or weight gain No extrapyramidal effects, hyperprolactinemia, hyperlipidemia, hyperglycemia, or weight gain Name three CYP 2D6 inhibitors. What should be done with aripiprazole if coadministered with any of these drugs? Name three CYP 2D6 inhibitors. What should be done with aripiprazole if coadministered with any of these drugs? Fluoxetine, paroxetine, quinidine Fluoxetine, paroxetine, quinidine The dose of aripiprazole should be reduced if coadministered with any of the above The dose of aripiprazole should be reduced if coadministered with any of the above Why isn’t aripiprazole the only antipsychotic used by now? Why 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. 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 1 st and 2 nd Generation antipsychotics? What are the differences between 1 st and 2 nd Generation antipsychotics? They are roughly equally effective in treating psychosis They are roughly equally effective in treating psychosis First generations have a higher incidence of extrapyramidal effects, while second generation have a higher incidence of weight gain, hyperglycemia, and hyperlipidemia First generations have a higher incidence of extrapyramidal effects, while second generation have a higher incidence of weight gain, hyperglycemia, and hyperlipidemia Second generation drugs are about 10x as expensive Second generation drugs are about 10x as expensive

17 Lithium Carbonate How long does it take for lithium carbonate to work? What percentage of patients get their mood stabilized? How long does it take for lithium carbonate to work? What percentage of patients get their mood stabilized? 2-3 weeks 2-3 weeks Normalizes the mood of 80% of patients Normalizes the mood of 80% of patients What do you do if a patient is suffering from “an acute manic attack” currently? What 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 stabilized Use an antipsychotic first, then introduce lithium later as the patient becomes stabilized The low therapeutic index and severe toxicity of lithium require a cooperative and stable patient The low therapeutic index and severe toxicity of lithium require a cooperative and stable patient Can lithium be used in patients with recurrent depression without mania? Can lithium be used in patients with recurrent depression without mania? According to this lecture yes, but it is much more dangerous than the SSRIs. 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? 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. 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. Other hypotheses include effects on ion transport or on serotonin and dopamine systems. What is the half life of lithium? What is the half life of lithium? About 20 hours About 20 hours What is the therapeutic window of lithium? What is the therapeutic window of lithium? 0.9 to 1.4 mEq/L 0.9 to 1.4 mEq/L

18 Lithium toxicities At what dose of lithium is toxicity first noticed? What is the treatment for lithium toxicity? At 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) 1.5 mEq/L (severe toxicity at 2.0 mEq/L) There is no specific treatment There is no specific treatment What three toxicity symptoms are diagnostic of lithium toxicity? What other symptoms occur? What three toxicity symptoms are diagnostic of lithium toxicity? What other symptoms occur? Coarse tremor, hyperreflexia, and slurred speech Coarse tremor, hyperreflexia, and slurred speech Vomiting, profuse diarrhea, arrhythmia, hypotension, ataxia, mental confusion, cranial nerve and focal neurologic deficits, coma, convulsions, death Vomiting, profuse diarrhea, arrhythmia, hypotension, ataxia, mental confusion, cranial nerve and focal neurologic deficits, coma, convulsions, death What side effects are common at therapeutic doses? What side effects are common at therapeutic doses? Nausea, diarrhea, drowsiness, hypothyroidism, polydipsia and polyuria, weight gain, cognitive blunting, birth defects Nausea, diarrhea, drowsiness, hypothyroidism, polydipsia and polyuria, weight gain, cognitive blunting, birth defects Is lithium secreted in breast milk? Is lithium secreted in breast milk? Yes Yes In which patients should lithium be used “with caution”? In which patients should lithium be used “with caution”? Patients needing a low sodium diet and those in the first trimester of pregnancy Patients needing a low sodium diet and those in the first trimester of pregnancy

19 Other Drugs What are two alternative drugs for bipolar disorder? What are two alternative drugs for bipolar disorder? Carbamazepine and valproic acid Carbamazepine and valproic acid Why isn’t carbamazepine a great choice? Why isn’t carbamazepine a great choice? A controlled study in the VA system has shown it to be ineffective. A controlled study in the VA system has shown it to be ineffective. Why might you use valproic acid (Depakote) instead of lithium? 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. 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. Long term efficacy has not been determined.

20 Dementia How many americans are affected by dementia? How many americans are affected by dementia? 4.5 million americans 4.5 million americans 100 billion dollars annually 100 billion dollars annually What is dementia? What 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. 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 solving Language, visuospatial, calculation, judgment, problem solving What are the three most common forms of dementia in order of most to least? What are the three most common forms of dementia in order of most to least? Alzheimer’s (60-80%), vascular dementia, lewy body dementia Alzheimer’s (60-80%), vascular dementia, lewy body dementia What 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)? What 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)? Acetylcholine Acetylcholine Nucleus basalis of meynert, which is the major source of Ach to the cortex. Nucleus basalis of meynert, which is the major source of Ach to the cortex. Name the cholinesterase inhibitors. Name the cholinesterase inhibitors. Tacrine, donepezil, rivastigmine, galantamine Tacrine, donepezil, rivastigmine, galantamine Name the NMDA receptor antagonist. Name the NMDA receptor antagonist. Memantine Memantine Name all the other drugs that are FDA approved for the treatment of Alzheimer’s disease. Name all the other drugs that are FDA approved for the treatment of Alzheimer’s disease. There are none There are none

21 Alzheimer’s Disease What is the first clinical feature of Alzheimer’s? What is the first clinical feature of Alzheimer’s? Impairment of short-term memory Impairment of short-term memory Is a deficiency of acetylcholine critical in the genesis of the symptoms of alzheimer’s disease? Is a deficiency of acetylcholine critical in the genesis of the symptoms of alzheimer’s disease? According to the cholinergic hypothesis, yes. According to the cholinergic hypothesis, yes. How does Tacrine funciton? How does Tacrine funciton? Centrally acting, noncompetitive, reversible cholinesterase inhibitor Centrally acting, noncompetitive, reversible cholinesterase inhibitor Also blocks reuptake of dopamine, NE, and serotonin. Inhibits MAO Also blocks reuptake of dopamine, NE, and serotonin. Inhibits MAO Blocks sodium and potassium channels Blocks sodium and potassium channels Partial muscarinic agonist Partial muscarinic agonist What is Tacrine’s half life? What is Tacrine’s half life? hours hours What is the most important adverse effect of Tacrine? What adverse effects are common? What is the most important adverse effect of Tacrine? What adverse effects are common? 50% of patients get hepatic toxicity 50% of patients get hepatic toxicity SLUD- salivation, lacrimation, urination, defecation SLUD- salivation, lacrimation, urination, defecation Nausea, vomiting, diarrhea, headache, myalgia, ataxia Nausea, vomiting, diarrhea, headache, myalgia, ataxia

22 Donepezil How does donepezil work? How does donepezil work? Noncompetitive, reversible inhibitor of acetylcholinesterase Noncompetitive, reversible inhibitor of acetylcholinesterase What is donepezil’s half life? What is donepezil’s half life? 70 hours 70 hours Why is donepezil better than tacrine? Why is donepezil better than tacrine? Donepezil does not cause hepatic toxicity Donepezil does not cause hepatic toxicity What type of inhibitor is rivastigmine? What type of inhibitor is rivastigmine? It is a “carbamate” inhibitor of acetylcholinesterase It is a “carbamate” inhibitor of acetylcholinesterase It is thus metabolized by acetylcholine to a decarbamylated product It is thus metabolized by acetylcholine to a decarbamylated product What are the adverse effects of rivastigmine? What are the adverse effects of rivastigmine? Nausea, vomiting, diarrhea, abdominal pain, anorexia, weight loss Nausea, vomiting, diarrhea, abdominal pain, anorexia, weight loss No hepatic toxicity No hepatic toxicity

23 Galantamine Use some crazy chemestry words and a flower to describe Galantamine. Use some crazy chemestry words and a flower to describe Galantamine. It is a tertiary alkaloid and phenanthrene derivative extracted from daffodial bulbs It is a tertiary alkaloid and phenanthrene derivative extracted from daffodial bulbs Describe the mechanism of Galantamine. Describe the mechanism of Galantamine. Reversible, competitive inhibitor of central acetylcholinesterase. Reversible, competitive inhibitor of central acetylcholinesterase. Also a nicotine receptor agonist (unknown significance) Also a nicotine receptor agonist (unknown significance) What liver system metabolizes Galantamine? What liver system metabolizes Galantamine? CYP 2D6 and 3A4 (can get toxicity in patients w/o 2D6) CYP 2D6 and 3A4 (can get toxicity in patients w/o 2D6) What unique side effect does Galantamine have? 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 In this class, it’s the only one listed to cause bradycardia. Other side effects are typical for a AchE

24 Memantine What patient population (severity of disease) are helped by Memantine? What patient population (severity of disease) are helped by Memantine? Moderate to severe Alzheimer’s disease patients are helped by memantine. Moderate to severe Alzheimer’s disease patients are helped by memantine. Describe the mechanism of memantine. Why does this help? 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) 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 neurons Excess NMDA activity is thought to be toxic to neurons, and to play a role in dying neurons reaching out and hurting their neighbor neurons What clinical benefit does memantine cause? What is its half life and elimination mode? What clinical benefit does memantine cause? What is its half life and elimination mode? Some reduced rate of cognitive deterioration (maybe) Some reduced rate of cognitive deterioration (maybe) hours, excreted in urine hours, excreted in urine. Describe memantine’s side effects? Describe memantine’s side effects? Dizziness, headache, constipation, hallucinations, confusion Dizziness, headache, constipation, hallucinations, confusion

25 Other stuff Which of the vitamin, antioxidant, and ginko biloba “medicines” have been shown to help with Alzheimer’s disease? Which of the vitamin, antioxidant, and ginko biloba “medicines” have been shown to help with Alzheimer’s disease? None of them None of them What molecule is the toxic end product of beta secretase and gamma secretase cleavage of APP? What molecule is the toxic end product of beta secretase and gamma secretase cleavage of APP? Aβ-42 Aβ-42 Do we have any useful inhibitors of beta secretase or gamma secretase? Do we have any useful inhibitors of beta secretase or gamma secretase? Nope Nope Do antibodies to Aβ induce clerance of the molecule? What bad thing happened in the (human) clinical study? Do antibodies to Aβ induce clerance of the molecule? What bad thing happened in the (human) clinical study? Yes, in a mouse model anyway. Yes, in a mouse model anyway. Caused meningoencephalitis in 6% of patients Caused meningoencephalitis in 6% of patients How awesome is Etanercept? How awesome is Etanercept? Super awesome Super awesome

26 Pharmacologic Management of Parkinsonism and Huntington’s

27 Parkinsonian basics In parkinson’s, symptoms start ______ and become _____. In parkinson’s, symptoms start ______ and become _____. Unilateral, bilateral Unilateral, bilateral What are the three diagnostic symtpoms of parkinson’s? What are the three diagnostic symtpoms of parkinson’s? Tremor (pill rolling, non-intention), rigidity (cogwheel), bradykinesia/akinesia Tremor (pill rolling, non-intention), rigidity (cogwheel), bradykinesia/akinesia What percent of adults over age 65 will get parkinson’s (idiopathic)? What percent of adults over age 65 will get parkinson’s (idiopathic)? About 1 percent About 1 percent What drugs cause drug-induced parkinsonism? What drugs cause drug-induced parkinsonism? MPTP, antipsychotic medications MPTP, antipsychotic medications What role does acetylcholine play in parkinson’s? What role does acetylcholine play in parkinson’s? Dopamine typically inhibits ACh excititory neurons, decreased dopamine causes an imbalance in this system. 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 ____. This is the rationale for the use of anticholinergic agents like ____ and ____. trihexyphenidyl and benzotropine trihexyphenidyl and benzotropine

28 Stages and Types What are the stages of parkinson’s disease? What are the stages of parkinson’s disease? 1. Unilateral symptoms, tremor of one upper limb, slight lateral tilt of upper body away from affected side, reduced arm swing, cogwheel. 2. Bilateral symptoms, stooped posture, more apparent motor symptoms 3. Shuffling gate becomes severe (falls) 4. And 5. continual decline in function – What are the four types of parkinsonism? – Postencephalitic parkinson’s Idiopathic Idiopathic – Drug induced – Miscellaneous (??)

29 Medications What were the first drugs used against parkinsonism? What were the first drugs used against parkinsonism? Anticholinergics Anticholinergics For whom are these medicines still used? For 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. 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? How long is the half life of L-dopa? 3 hours, metabolized to dopamine (peripherally) 3 hours, metabolized to dopamine (peripherally) What is the high end of the dosing spectrum with L-dopa? What is the high end of the dosing spectrum with L-dopa? At least 8-10 grams per day can be used. At least 8-10 grams per day can be used. How do you prevent or limit side effects? How do you prevent or limit side effects? By titrating the dose up very slowly By titrating the dose up very slowly What side effects are common with long term use of L-dopa? What side effects are common with long term use of L-dopa? Choreiform movements, mental confusion, delirium Choreiform movements, mental confusion, delirium N & V, orthostatic hypotension, arrhythmias also occur N & V, orthostatic hypotension, arrhythmias also occur N & V or N/V is nausea and vomiting N & V or N/V is nausea and vomiting What drug interactions with L-dopa are problematic? Which one is useful? What 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. 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. Carbidopa coadministration increases the percentage of L-dopa that crosses the BBB, reducing the necessary dose of L-dopa 7-10 fold.

30 Ergots How well does amantadine work for parkinsonism? What is it normally used for? What are its side effects. How well does amantadine work for parkinsonism? What is it normally used for? What are its side effects. Only useful for a couple of weeks Only useful for a couple of weeks Amantadine is an antiviral agent that also causes release of dopamine from dopamine neurons and has a little NMDA antagonism (half life 2-4 hours) Amantadine 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 hallucinations Headache, confusion, and hallucinations What is the mechanism of Bromocriptine and Pergolide? What is the difference in their mechanisms? What is the mechanism of Bromocriptine and Pergolide? What is the difference in their mechanisms? These drugs are direct acting dopamine agonists These drugs are direct acting dopamine agonists Bromocriptine is an agonist at D2 but an antagonist at D1, pergolide is an agonist at D1 and 2. Bromocriptine is an agonist at D2 but an antagonist at D1, pergolide is an agonist at D1 and 2. How are these drugs used? How are these drugs used? Bromocriptine or pergolide can be used alone or with L-dopa or with L-dopa + carbidopa Bromocriptine or pergolide can be used alone or with L-dopa or with L-dopa + carbidopa Pergolide may have a better benefit to risk ratio (or not) Pergolide may have a better benefit to risk ratio (or not) Why isn’t pergolide on the test? Why isn’t pergolide on the test? It causes a 6-fold increase in heart valve problems or something like that It causes a 6-fold increase in heart valve problems or something like that What is bromocriptine metabolized to? What is bromocriptine metabolized to? L-amphetamine and L-methamphetamine (which are much less potent and the D isomers) L-amphetamine and L-methamphetamine (which are much less potent and the D isomers) What are the side effects of bromocriptine? 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. 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? In whom is bromocriptine contraindicated? What is the other limiting factor? History of psychotic illness, recent myocardial infarction, peripheral vascular disease, and peptic ulcers History of psychotic illness, recent myocardial infarction, peripheral vascular disease, and peptic ulcers Cost- it is very expensive Cost- it is very expensive

31 What are the newer dopamine agonists? What are the newer dopamine agonists? Pramipexole and ropinirole Pramipexole and ropinirole Why are these better than the ergot derivatives? Why are these better than the ergot derivatives? They are better tolerated They are better tolerated What strange effect sometimes happens with these new dopamine agonists? What strange effect sometimes happens with these new dopamine agonists? Falling asleep during normal daytime activities Falling asleep during normal daytime activities How does Selegiline work? Why is this good? How does Selegiline work? Why is this good? It inhibits the B form of MAO It inhibits the B form of MAO The drug leaves the A form of MAO alone, which prevents the problem of hypertensive crisis The drug leaves the A form of MAO alone, which prevents the problem of hypertensive crisis Also some studies indicate that these drugs actually reverse some of the damage in parkinson’s disease Also some studies indicate that these drugs actually reverse some of the damage in parkinson’s disease

32 Yo-yo-yoing holidays What are the names of the (reversible) COMT inhibitors used? What are the names of the (reversible) COMT inhibitors used? Tolcapone and Entacapone Tolcapone and Entacapone What are these drugs used for? What 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”) 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? 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. 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” 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). 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? What is Peak dose dyskinesia? How is it treated? Abnormal, involuntary movements which occur 1-2 hours after dosing. May involve excess dopamine) Abnormal, involuntary movements which occur 1-2 hours after dosing. May involve excess dopamine) Smaller and more frequent doses Smaller and more frequent doses What is yo-yo-ing? What 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. 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. 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? How useful are drug holidays? Not shown to be helpful Not shown to be helpful

33 Huntington’s Chorea How many people get Huntington’s? At what age? How many people get Huntington’s? At what age? 1/50,000 1/50,000 Age years Age years What are the early symptoms of Huntingtons? What are the early symptoms of Huntingtons? catatonia, aggressive outbursts, psychotic behavior, exaggerated reflexes, good muscle strength, but weak tone catatonia, aggressive outbursts, psychotic behavior, exaggerated reflexes, good muscle strength, but weak tone catatonia What are the later symptoms? What are the later symptoms? Progressively worsening dementia, increased appetite without weight gain Progressively worsening dementia, increased appetite without weight gain What are the final stage symptoms? What are the final stage symptoms? Greatly increased diet with weight loss, rigid motor tone, death within years of onset of symptoms Greatly increased diet with weight loss, rigid motor tone, death within years of onset of symptoms What drugs improve the motor symptoms of Huntington’s? What drugs improve the motor symptoms of Huntington’s? Reserpine, phenothiazine and butyrophenone antipsychotics Reserpine, phenothiazine and butyrophenone antipsychotics What drugs make the motor symptoms worse? What drugs make the motor symptoms worse? L-dopa, anticholinergics, and dopamine agonists L-dopa, anticholinergics, and dopamine agonists

34 Non-steroidal Anti- inflammatory Drugs February 4, 2008

35 What is the mechanism of the NSAIDs? What is the mechanism of the NSAIDs? They all inhibit cyclooxygenase and subsequent prostaglandin and thromboxane synthesis. 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. 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 2 What’s the difference between COX-1 and 2 Cox 2 is an inducible form, whereas Cox-1 is present in every cell. Major sites of Cox-1 that result in toxicity are: Cox 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, kidney Platelets, blood vessles, stomach, kidney Theoretically, why are COX-2 inhibitors better than regular NSAIDs? Theoretically, why are COX-2 inhibitors better than regular NSAIDs? They don’t cause problems in places listed above. They don’t cause problems in places listed above.

36 What effect do prostaglandins have on pain? What effect do prostaglandins have on pain? Prostaglandins decrease pain threshold Prostaglandins decrease pain threshold What severity of pain are NSAIDs useful for? What 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 pain Effective against mild to moderate and dull aching pain, though they can be as effective as opiates in certain types of pain In jaw and mouth surgery NSAIDs are just as effective as opiates In jaw and mouth surgery NSAIDs are just as effective as opiates How do NSAIDs cause anti-inflammatory effects? How do NSAIDs cause anti-inflammatory effects? Inhibiting PGE2 and PGI2 reduces edema formation Inhibiting PGE2 and PGI2 reduces edema formation At high concentrations NSAIDs reduce neutrophil migration At high concentrations NSAIDs reduce neutrophil migration What mediates NSAIDs antipyretic effect? What mediates NSAIDs antipyretic effect? NSAIDs prevent PGE2 formation, which is believed to be responsible for altering the body temperature set point NSAIDs prevent PGE2 formation, which is believed to be responsible for altering the body temperature set point

37 Side effects What are NSAIDs used for? What are NSAIDs used for? Pain, primary dysmenorrhea, joint inflammation (side effects are a problem when used for inflammation in rheumatism), fever, sunburn Pain, primary dysmenorrhea, joint inflammation (side effects are a problem when used for inflammation in rheumatism), fever, sunburn What is the first line drug of choice for rheumatoid arthritis? What is the first line drug of choice for rheumatoid arthritis? Aspirin in high doses Aspirin in high doses What are the most common side effects of the NSAIDs? What causes these problems? What are the most common side effects of the NSAIDs? What causes these problems? GI distress, damge, bleeding/ulceration GI distress, damge, bleeding/ulceration Prostaglandins 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 lining Prostaglandins 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 lining What mediates NSAID renal effects? What 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. 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? 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. 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.

38 Salicylate What is the prototype Salicylate? How does it work? What is the prototype Salicylate? How does it work? Aspirin Aspirin It is an irreversible inhibitor of prostaglandin synthesis (binds COX nonselectively and irreversibly) It is an irreversible inhibitor of prostaglandin synthesis (binds COX nonselectively and irreversibly) What is special about aspirin’s nonreversible mechanism? 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. 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? What is aspirin metabolized to? How long is aspirin’s half life? What kinetics does aspirin follow? Salicylic acid (the active agent) Salicylic acid (the active agent) 15 minutes (salicylic acid has a half life of 3-4 hours) 15 minutes (salicylic acid has a half life of 3-4 hours) First order at low doses and zero order at high doses First order at low doses and zero order at high doses How does pH affect the distribution of aspirin? How does pH affect the distribution of aspirin? Decreased pH increases unionized drug available for distribution. Aspirin makes the blood more acidic. Decreased pH increases unionized drug available for distribution. Aspirin makes the blood more acidic.

39 Aspirin toxicities What 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? What 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 reactions Bleeding, decreased uric acid excretion, hypersensitivity reactions Salicylism, tinnitus (early warning sign), increased metabolic rate (uncoupled mitochondria) with consequent fever, hyperventilation and respiratory alkalosis Salicylism, tinnitus (early warning sign), increased metabolic rate (uncoupled mitochondria) with consequent fever, hyperventilation and respiratory alkalosis Moderate toxicity causes respiratory depression with respiratory, chemical, and metabolic acidosis (which is exacerbated by the previous alkalosis). Moderate 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). 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? How does one treat salicylate intoxication? Cool, rehydrate, correct acid base and electrolyte imbalance Cool, rehydrate, correct acid base and electrolyte imbalance Prevent further absorption (emesis/lavage) Prevent further absorption (emesis/lavage) Alkalinize the urine to increase excretion Alkalinize the urine to increase excretion Hemodialysis Hemodialysis Diazepam for convulsions Diazepam for convulsions

40 NSAID varieties For whom is aspirin contraindicated? For whom is aspirin contraindicated? Patients with: renal disease, bleeding disorders, hypersensitivity, gout, and young children during or following a viral infection Patients with: renal disease, bleeding disorders, hypersensitivity, gout, and young children during or following a viral infection Is ibuprofen another NSAID? How effective of an analgesic is it? Of an anti- inflammatory? What are ibuprofen’s side effects? Is ibuprofen another NSAID? How effective of an analgesic is it? Of an anti- inflammatory? What are ibuprofen’s side effects? Yes Yes At low dose, it is more effective than aspirin at analgesia At low dose, it is more effective than aspirin at analgesia At high doses, its anti-inflammatory action is just as good as aspirin At high doses, its anti-inflammatory action is just as good as aspirin GI irritation and bleeding, rash, tinnitus w/dizziness, agranulocytosis, aplastic anemia, renal failure, interstitial nephritis, nephrotic syndrome. GI 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? What’s good about Naproxen? What’s bad about Naproxen? Long half life (13 hours) Long half life (13 hours) Intermediate potency (

41 What is ketoralac used for? What 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 opiate 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 opiate What are COX-2 inhibitors used for? What are COX-2 inhibitors used for? RA, OA, acute pain, dysmenorrhea RA, OA, acute pain, dysmenorrhea What happened to the COX-2 inhibitors? What 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 effects They are prothrombotic, and in clinical trials they have been shown to cause a 2-4 fold increase in the incidence of cardiovascular side effects It is suspected that selective COX-2 inhibitors have selective inhibitor activity against prostacyclin (PGI2) synthase (as opposed to TXA2). This makes them prothrombotic. It 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? What is Meloxicam? It is a partially selective COX-2 inhibitor with a 20 hour half life It is a partially selective COX-2 inhibitor with a 20 hour half life

42 What is 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. 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 mediators Granulocytes release lysosomal enzymes and inflammatory mediators What is used for acute treatment of gout (2 drugs)? How does each work? What is used for acute treatment of gout (2 drugs)? How does each work? Cochicine Cochicine Inhibits release of chemotactic and inflammatory mediators, inhibiting neutrophil activation. (highly toxic with low therapeutic index) Inhibits release of chemotactic and inflammatory mediators, inhibiting neutrophil activation. (highly toxic with low therapeutic index) Indomethacin Indomethacin Drug of choice to reduce inflammation. Why indomethacin? Drug of choice to reduce inflammation. Why indomethacin? Others will inhibit uric acid excretion Others will inhibit uric acid excretion What drugs are used to prevent gout? What drugs are used to prevent gout? Urocusuric agents prevent renal tubular reabsorption of urate Urocusuric agents prevent renal tubular reabsorption of urate Probenecid and sulfinpyrazone Probenecid and sulfinpyrazone These drugs are not for patiets who already produce and excrete large amounts or urate These drugs are not for patiets who already produce and excrete large amounts or urate Keep urine volume high and pH > 6 Keep urine volume high and pH > 6 Allopurinol Allopurinol Inhibits xanthine oxidase, blocks urate synthesis Inhibits xanthine oxidase, blocks urate synthesis GI irritation and skin reactions GI irritation and skin reactions

43 Management of Acetominophen overdose Dr. Laura James

44 What is the major cause of acute liver failure in the United States today? What is the major cause of acute liver failure in the United States today? Acetominophen toxicity (roughly 50% in 2003) Acetominophen toxicity (roughly 50% in 2003) Acetominophen is also one of the most common causes of pharmaceutical product poisoning Acetominophen is also one of the most common causes of pharmaceutical product poisoning What is the most studied drug in toxicology? What is the most studied drug in toxicology? Acetominophen Acetominophen How long does absorption take of a therapeutic dose? Of an overdose? How 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 hours A therapeutic dose is completely absorbed within 1 hour, but overdose can delay absorption up to 4 hours What order kinetics does acetominophen follow? What is the half life? What order kinetics does acetominophen follow? What is the half life? It follows first order kinetics (exception in liver failure, 0 order kinetics) It follows first order kinetics (exception in liver failure, 0 order kinetics) 2.5 to 4 hours 2.5 to 4 hours

45 What is the mechanism of acetominophen? What is the mechanism of acetominophen? Mechanism is somewhat unknown, some recent evidence indicates a role in the central serotonin system. 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. 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? What is good about acetominophen from a side effect stand point? It is not a gastric irritant and has no effect on platelets It is not a gastric irritant and has no effect on platelets What is the mechanism of acetominophen toxicity? What is the mechanism of acetominophen toxicity? Metabolism causes toxcity, (toxification by the liver) Metabolism causes toxcity, (toxification by the liver) Describe the metabolism of acetominophen Describe the metabolism of acetominophen At therapuetic doses >90 % undergoes glucuronidation and sulfation and is eliminated by the kidneys At therapuetic doses >90 % undergoes glucuronidation and sulfation and is eliminated by the kidneys Small remainder is metabolized by CYP P450 to NAPQI, a toxic metabolite. NAPQI is then detoxified by glutathione in non-overdose situations. Small 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. CYP 2E1 is the primary P450 system involved.

46 Describe metabolism of Ac in overdose and the mechanism of toxicity (4 steps). Describe metabolism of Ac in overdose and the mechanism of toxicity (4 steps). 1. Normal pathways are overwhelemed, build up of NAPQI occurs 2. Glutathione is depleted 3. NAPQI binds to proteins (hepatocytes), forming adducts. 4. Cell death Agewise, who is more susceptible to acetominophen poisoning? Agewise, who is more susceptible to acetominophen poisoning? Adults are more susceptible to acetominophen toxicity, whereas kids seem to be “relatively protected” Adults are more susceptible to acetominophen toxicity, whereas kids seem to be “relatively protected” How does ethanol increase the risk of acetominophen toxicity? How does ethanol increase the risk of acetominophen toxicity? Long term use of ethanol induces CYP 2E1 by 2-3 fold Long term use of ethanol induces CYP 2E1 by 2-3 fold Binge use of alcohol at the time of overdose may decrease NAPQI formation Binge use of alcohol at the time of overdose may decrease NAPQI formation What is a toxic dose of acetominophen in a child? In an adult? Is this information on the test? What is a toxic dose of acetominophen in a child? In an adult? Is this information on the test? 150 mg/kg 150 mg/kg 7.5 grams 7.5 grams Max Therapeutic dose is 90 mg/kg/day in a child or 4 grams per day for adult Max Therapeutic dose is 90 mg/kg/day in a child or 4 grams per day for adult yes yes

47 Describe the four phases of acetominophen toxicity. Describe the four phases of acetominophen toxicity hours 1. Nausea, vomiting, elevation of hepatic transaminases, or asymptomatic hours 1. Abdominal tenderness in RUQ. Elevated hepatic enzymes. Clotting factors impaired. May have renal involvement hours 1. Sequelae of hepatic injury: jaundice, coagulation defects, hepatic encephalopathy, renal failure, death will happen in this phase 1. Hard to get history at this point. If you show up to the hospital now, it is hard to treat you days 1. They get better and the liver fully recovers

48 Treatment What kind of liver damage is done by acetominophen toxicity (a path. term)? What kind of liver damage is done by acetominophen toxicity (a path. term)? Centrilobular necrosis Centrilobular necrosis Describe the treatment of acetominophen poisoning. Why is it important to treat quickly? What is the major adverse effect of this drug? Describe the treatment of acetominophen poisoning. Why is it important to treat quickly? What is the major adverse effect of this drug? N-acetylcysteine (NAC) N-acetylcysteine (NAC) Works at the glutathione step as a glutathione substitute to prevent “adduct” formation Works at the glutathione step as a glutathione substitute to prevent “adduct” formation IV NAC got approved in 2004 IV NAC got approved in 2004 Efficacy is highly dependent on the time of NAC relative to the overdose. Efficacy is highly dependent on the time of NAC relative to the overdose. Treatment within 10 hours –6% risk of toxicity Treatment within 10 hours –6% risk of toxicity hours after overdose—26.4% risk of toxicity hours after overdose—26.4% risk of toxicity Vomiting is the major side effect. Anaphylaxis is also a possibility, especially with IV dosing. Vomiting 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? What treatments can be effective if administered within two hours of the overdose? Activated charcoal Activated charcoal Do you treat the patients nausea and vomiting? Do you treat the patients nausea and vomiting? yes yes

49 What is the maximum dose of acetominophen for adults? For children? What is the maximum dose of acetominophen for adults? For children? 4 grams/day adults or 90mg/kg/day in children 4 grams/day adults or 90mg/kg/day in children What percentage of acetominophen related acute liver failure is caused by opiod/acetominophen mixes? What percentage of acetominophen related acute liver failure is caused by opiod/acetominophen mixes? 50 % 50 % Should you remember the numbers from this lecture? Should you remember the numbers from this lecture? Oh yeah, big time. And remember/be able to use that graph. Oh yeah, big time. And remember/be able to use that graph.

50 Opioid analgesics and antagonists Paul L. Prather—Feb 05, 2008

51 What is the difference between an opioid and an opiate? What 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. 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? What is the mechanism of the opioid receptors? These receptors hyperpolarize neurons which causes analgesia These receptors hyperpolarize neurons which causes analgesia They open K channels to hyperpolarize the cell, and some close Ca channels They open K channels to hyperpolarize the cell, and some close Ca channels They are G protein coupled receptors They are G protein coupled receptors

52 Describe the three receptor types. Mu receptors Mu receptors 99% of opioids act at this receptor 99% of opioids act at this receptor Cause supraspinal analgesia, miosis, respiratory depression, euphoria, dependence Cause supraspinal analgesia, miosis, respiratory depression, euphoria, dependence Delta Delta Less well defined, also produces supraspinal and spinal analgesia, possibly less dependence Less well defined, also produces supraspinal and spinal analgesia, possibly less dependence Sometimes agonists cause seizure Sometimes agonists cause seizure Kappa Kappa Spinal and some supraspinal analgesia. Weak miosis, sedation, some respiratory depression, dysphoria Spinal and some supraspinal analgesia. Weak miosis, sedation, some respiratory depression, dysphoria

53 Receptorology What receptors have the highest affinity for beta-endorphins? What receptors have the highest affinity for beta-endorphins? These endogenous opioids have the highest affinity for mu and delta receptors. These endogenous opioids have the highest affinity for mu and delta receptors. What receptor do enkephalins have the most affinity for? What receptor do enkephalins have the most affinity for? Delta receptors Delta receptors What about dynorphins What about dynorphins Kappa receptors Kappa receptors Are mu receptor agonists better for dull pain or sharp pain? Are mu receptor agonists better for dull pain or sharp pain? Mu agonists are better for dull pain Mu agonists are better for dull pain What are the three useful effects of exogenous opiate drugs? What 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) 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 activation GI tract: increase tone and decrease motility due to mu receptor activation Great for anti-diarrheal but causes constipation in chronic pain patients Great for anti-diarrheal but causes constipation in chronic pain patients Antitussive Effects: suppression of cough Antitussive Effects: suppression of cough

54 What bad things happen acutely after one takes opioids? What bad things happen acutely after one takes opioids? Respiratory brain stem center depression Respiratory brain stem center depression Decreased response to carbon dioxide, decreased automaticity Decreased response to carbon dioxide, decreased automaticity Causes death in overdose Causes death in overdose Miosis Miosis Stimulation of edinger-westphal nucleus of 3 rd cranial nerve. Little tolerance develops to pinpoint pupils. Stimulation of edinger-westphal nucleus of 3 rd cranial nerve. Little tolerance develops to pinpoint pupils. Sedation and Euphoria Sedation and Euphoria Not mutually exclusive. Sedation may progress to sleep and coma, while euphoria plays a role in reinforcement and addiction Not mutually exclusive. Sedation may progress to sleep and coma, while euphoria plays a role in reinforcement and addiction Emesis Emesis Direct stimulation of mu receptors in the chemoreceptor trigger zone. Also potentiate vestibular stimulation. Direct stimulation of mu receptors in the chemoreceptor trigger zone. Also potentiate vestibular stimulation. Cardiovascular Cardiovascular Release of histamine may result in mild hypotension. Release of histamine may result in mild hypotension. Urinary retention Urinary retention Inhibition of urinary voiding reflex (tolerance develops) Inhibition of urinary voiding reflex (tolerance develops) Biliary spasm Biliary spasm Chest wall rigidity Chest wall rigidity What receptor is responsible for most of the toxicities listed above? What receptor is responsible for most of the toxicities listed above? The Mu receptor The Mu receptor

55 Tolerance and Dependence Define tolerance. Describe the clinical tolerance expected with opiate administration. Which 2 effects do not develop tolerance? 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. 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. 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?) Miosis and constipation (I think?) Describe opioid dependence. Describe opioid dependence. Dependence is produced by repeated opiod exposure that manifests in a withdrawal syndrome when chronic exposure is abruptly discontinued. 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. 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. What are the two types of dependence? Describe withdrawal in regard to opioids. Behavioral dependence Behavioral dependence Physical dependence Physical dependence Withdrawal begins 6 hours after last dose, peaks at 48 hours, declines for 10 days Withdrawal begins 6 hours after last dose, peaks at 48 hours, declines for 10 days Sweating, nausea, vomiting, ccramps, shivering, shakes, restlessness. Sweating, nausea, vomiting, ccramps, shivering, shakes, restlessness. Not life threatening, reversible in any stage Not life threatening, reversible in any stage

56 Chemistry What is the dependence mechanism? What is the dependence mechanism? cAMP upregulation is a compensitory mechanism in chronic opioid administration. 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? What is the prototype mu agonist? How can you turn morphine into heroin? Into Naloxone? How can you increase potency? Increase kappa effects? Morphine Morphine Acetylation at 3- and 6 increases potency and creates heroin Acetylation at 3- and 6 increases potency and creates heroin Allyl substitutions at the N position (position 17) produces antagonists (naloxone) Allyl substitutions at the N position (position 17) produces antagonists (naloxone) Stabilizing the C ring can greatly increase potency Stabilizing the C ring can greatly increase potency Loss of C ring increases kappa effects Loss of C ring increases kappa effects Which form of opioids are active? Which form of opioids are active? The Levo forms are active The Levo forms are active The dextro forms are much less active (hence dextromethorphan as OTC cough medicine) The dextro forms are much less active (hence dextromethorphan as OTC cough medicine)

57 Describe the pharmacokinetics of morphine? Describe the pharmacokinetics of morphine? It has poor oral absorption and large first pass effect. 2-3 hour half life. It has poor oral absorption and large first pass effect. 2-3 hour half life. Describe heroin Describe heroin Is 5-10 times more potent than morphine Is 5-10 times more potent than morphine It has greater lipid solubility than morphine It has greater lipid solubility than morphine It has a very short (½ hour) half life It has a very short (½ hour) half life Shorter half life equals worse withdrawal symptoms Shorter half life equals worse withdrawal symptoms Describe codeine. Describe codeine. Orally effective (60% oral bioavailability) Orally effective (60% oral bioavailability) 2-4 hour half life 2-4 hour half life What is different about meperidine (demerol)? What 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) 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. Meperidine has an active metabolite (normeperidine) that is excitatory and works at non-opioid receptors.

58 How potent are fentanyl and congeners? What is their onset time? How potent are fentanyl and congeners? What is their onset time? These are very potent ( x more potent than morphine) and very short acting. These are very potent ( x more potent than morphine) and very short acting. Their onset is between 5 and 15 minutes. Their onset is between 5 and 15 minutes. Great for rigging horse races. Great for rigging horse races. Why is methadone good for addicts? Why is methadone good for addicts? Used for maintenance therapy for opioid addicts due to oral activity and long duration of action. Used for maintenance therapy for opioid addicts due to oral activity and long duration of action. What is propoxyphene (Darvocet)? What is propoxyphene (Darvocet)? It is the only opioid with a dextro active form (ON TEST) It is the only opioid with a dextro active form (ON TEST) Is used orally and is less potent than morphine Is used orally and is less potent than morphine

59 A Mixed Agonist/Antagonist and a Partial Agonist What is Pentazocine? For what and mixed with what is it used? 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 receptors Partial agonist/antagonist at Mu receptors, as well as analgesic activity at Kappa receptors Often combined with naloxone for addicts Often combined with naloxone for addicts What is buprenorphine used for? What is its mechanism? What is buprenorphine used for? What is its mechanism? Is sometimes used as a step down from methadone therapy in addicts. Is sometimes used as a step down from methadone therapy in addicts. It is also an effective analgesic in non-addicts It is also an effective analgesic in non-addicts It is a partial agonist at mu receptors and antagonist at kappa receptors It is a partial agonist at mu receptors and antagonist at kappa receptors

60 Naloxone Why is naloxone a good drug for opioid toxicity? 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. 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? What is even better about Naltrexone? Naltrexone is useful because it has a much longer duration of action. Recently used for alcoholism. Naltrexone is useful because it has a much longer duration of action. Recently used for alcoholism. What is unique about oxycodone? What is unique about oxycodone? It is a controlled release analgesic with much publicity on abuse potential. It is a controlled release analgesic with much publicity on abuse potential.

61 Pain Medicine Dr. Firnhaber—Feb 05, 2008

62 Pain! What is pain? 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. 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 treated Pain is usually considered a symptom but is rarely directly treated What makes pain “chronic”? What are the two categories of chronic pain? What 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) Chronic pain lasts beyond the time that normal healing occurs (typically 3-6 months) Maglignant chronic pain Maglignant chronic pain Non-malignant chronic pain (benign pain, 1/3 of americans) Non-malignant chronic pain (benign pain, 1/3 of americans) Includes headaches, low-back pain, arthritis, and others Includes headaches, low-back pain, arthritis, and others

63 Pain Types What type of pain is the most difficult to treat? What type of pain is the most difficult to treat? Non-malignant chronic pain Non-malignant chronic pain What are the types of non-malignant chronic pain? What are the types of non-malignant chronic pain? Nociceptive pain- responds well to opioids Nociceptive pain- responds well to opioids Somatic- intense and discrete, well localized, often aching or throbbing. Somatic- 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. Visceral- diffuse, episodic, and poorly localized. This pain involves the internal organs and is propagated by sympathetic fibers. Neuropathic Neuropathic Pain 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. Pain 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.Allodynia It does respond to opioids, but not as well as nociceptive pain It does respond to opioids, but not as well as nociceptive pain

64 Treatment Approaches What are the “conservative” treatments of pain? What are the “conservative” treatments of pain? NSAIDS or COX-2 inhibitors, muscle relaxants, membrane stabilizers, TCA/Anticonvulsants NSAIDS or COX-2 inhibitors, muscle relaxants, membrane stabilizers, TCA/Anticonvulsants What are the other treatments of pain? What are the other treatments of pain? Physical therapy, interventional therapy, or opioids Physical therapy, interventional therapy, or opioids What makes methodone the best pain killer? What makes methodone the best pain killer? It is both a mu agonist and a minor NMDA antagonist It is both a mu agonist and a minor NMDA antagonist Why is tramadol considered an opioid? Why is tramadol considered an opioid? While it has other functions, it is also a weak mu receptor agonist. 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? How can you decrease pain in patients who are refractory to potent parenteral opioids? Either intrathecal opioids or nerve destruction Either intrathecal opioids or nerve destruction

65 Toxicity and Addiction What organ toxicities are common with long term opioid therapy? What organ toxicities are common with long term opioid therapy? None, actually safer in this respect than NSAIDs None, actually safer in this respect than NSAIDs May cause some impairment of immune function, but the clinical importance of this is minimal May cause some impairment of immune function, but the clinical importance of this is minimal What two effects do not get tolerance in long term opioid therapy? What two effects do not get tolerance in long term opioid therapy? miosis and decreased gastric motility miosis and decreased gastric motility What is addiction? What 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 relapse A behavioral pattern characterized by overwhelming involvement with the use of a drug, the securing of the supply, and the high tendancy to relapse Most scientists say it is incurable/permanent Most scientists say it is incurable/permanent What is the prevalence of addiction? What is the prevalence of addiction? 19% in chronic pain patient, 16% of general public 19% in chronic pain patient, 16% of general public

66 Dependence What is physcial dependence? What is physcial dependence? The potential for an abstinence syndrome, or withdrawal following abrupt dose reduction, discontinuation, or administration of an antagonist. 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? 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 often Yes, again this is why methodone does not develop tolerance very often How does one manage tolerance? How does one manage tolerance? Start with a differential diagnosis and ruling out any new problem that is causing pain Start with a differential diagnosis and ruling out any new problem that is causing pain Next you can increase the dose or use an alternative opioid at a reduced dose Next you can increase the dose or use an alternative opioid at a reduced dose Or you can use alternative pain management stratagies (drug holidays combined with other drugs) Or you can use alternative pain management stratagies (drug holidays combined with other drugs) What is pseudoaddiction? 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 interventions 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 interventions Looks like drug-seeking, but different in that when higher doses are provided and pain is effectively treated, these behaviors disappear Looks like drug-seeking, but different in that when higher doses are provided and pain is effectively treated, these behaviors disappear

67 How is the maximum dose of opioids determined? How is the maximum dose of opioids determined? Keep going up until pain is effectively treated or side effects are limiting Keep going up until pain is effectively treated or side effects are limiting What is the financial problems with opioids? What is the financial problems with opioids? All opioids have a street value, 2.6 million americans report using analgesics for non-medical reasons All opioids have a street value, 2.6 million americans report using analgesics for non-medical reasons How might one treat “complex regional pain syndrome” of the upper extremity? How might one treat “complex regional pain syndrome” of the upper extremity? Stellate ganglion and lumbar sympathetic block Stellate ganglion and lumbar sympathetic block

68 Interventional crap What are the following indicated for? What are the following indicated for? Celiac block Celiac block Acute and chronic pancreatitis, pancreatic carcinoma, upper abdominal malignancies Acute and chronic pancreatitis, pancreatic carcinoma, upper abdominal malignancies Lumbar sympathetic Lumbar sympathetic Complex regional pain syndromes of the lower extremity, vascular insufficiency Complex regional pain syndromes of the lower extremity, vascular insufficiency Superior hypogastric Superior hypogastric Mid-gut and colon malingnancies, sometimes rectal and pelvic malignancies Mid-gut and colon malingnancies, sometimes rectal and pelvic malignancies For 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. For 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.

69 Atypical delivery Why is neuraxial drug delivery sometimes preferable? When is it indicated? Why 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 effects It can be effective for multiple pains, is nondestructive, requires lower doses with lower side effects When 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 expectations When 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 expectations What is the most used local anesthetic for intrathecal pain management? What is the most used local anesthetic for intrathecal pain management? Bupivacaine Bupivacaine What adrenergic agent if especially useful in intrathecal use? What adrenergic agent if especially useful in intrathecal use? Clonidine (FDA approved for pain) Clonidine (FDA approved for pain) What muscle relaxant is good for cerebral palsy? What is the new FDA approved drug for intrathecal pain? What muscle relaxant is good for cerebral palsy? What is the new FDA approved drug for intrathecal pain? Baclofen Baclofen ziconotide ziconotide There is way more information on pages , but I’m probably not learning it. There is way more information on pages , but I’m probably not learning it.

70 Nicotine and Other stimulants Dr. Owens, Feb 05, 2008

71 Stimulants of abuse What are the two main forms of abused cocaine? Describe each. What are the two main forms of abused cocaine? Describe each. Cocaine hydrochloride Cocaine hydrochloride Can be sniffed as a “line” or “shot” iv Can be sniffed as a “line” or “shot” iv Sniffing can make your nose rot off (vasoconstrictor) Sniffing can make your nose rot off (vasoconstrictor) Cocaine free base Cocaine free base Crack or rock cocaine, which is volatilized for inhalation. Onset is even faster Crack or rock cocaine, which is volatilized for inhalation. Onset is even faster Who developed free-basing? Who 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. 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? What makes cocaine/methamphetamine so addictive? These drugs kidnap people’s reward centers. Many addiction scientist relate it to the experience of an orgasm. These drugs kidnap people’s reward centers. Many addiction scientist relate it to the experience of an orgasm. Describe the pharmacological actions of cocaine. Describe the pharmacological actions of cocaine. Initially, there is a very pleasurable “rush,” a feeling with sexual overtones Initially, there is a very pleasurable “rush,” a feeling with sexual overtones Euphoria, increased energy, increased sensory awareness, decreased need for sleep, anorexia, increased activity Euphoria, increased energy, increased sensory awareness, decreased need for sleep, anorexia, increased activity Post euphoria—Increased anxiety, suspicion of others, delusions, paranoia Post euphoria—Increased anxiety, suspicion of others, delusions, paranoia Increased heart rate, blood pressure, incidence of stroke Increased heart rate, blood pressure, incidence of stroke

72 Kinetics Describe a “run.” Describe a “run.” A person uses the drug until all available drug is consumed. A person uses the drug until all available drug is consumed. What drugs are commonly combined with cocaine? Why? What drugs are commonly combined with cocaine? Why? Alcohol, sedative hypnotics, opiates, marijuana Alcohol, sedative hypnotics, opiates, marijuana Used to treat the side effects of the excess stimulation caused by cocaine. Used to treat the side effects of the excess stimulation caused by cocaine. What is the half life of cocaine? What is the half life of cocaine? 45 minutes 45 minutes Most addicts like the initial rush and do not care for the next minutes of feeling. Most 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? 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. 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 Cocaethylene is created when cocaine and alcohol are coadministered

73 Tolerance and Dependence Describe cocaine tolerance. Describe cocaine tolerance. Minimal tolerance develops, and there is some evidence of sensitization to some effect Minimal tolerance develops, and there is some evidence of sensitization to some effect Describe the physical dependence to cocaine. Describe 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. 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? What is the pharmacologic mechanism of cocaine? Cocaine blocks the reuptake of released catecholamines and 5- hydroxytryptamine as well as dopamine reuptake Cocaine blocks the reuptake of released catecholamines and 5- hydroxytryptamine as well as dopamine reuptake Blocking dopamine reuptake seems to be responsible for CNS effects and abuse potential Blocking dopamine reuptake seems to be responsible for CNS effects and abuse potential Describe the acutely cocaine overdosed patient. Describe the acutely cocaine overdosed patient. The patient experiences paranoid aggression and cardiovascular crisis; he is dangerous. The patient experiences paranoid aggression and cardiovascular crisis; he is dangerous. What are the new developments in the treatment and prevention of cocaine dependence? What are the new developments in the treatment and prevention of cocaine dependence? Cocaine antibodies to act as a pharmacokinetic antagonist Cocaine antibodies to act as a pharmacokinetic antagonist

74 Amphetamine What isomer of amphetamine is most addictive? What isomer of amphetamine is most addictive? d or (+) isomer d or (+) isomer Why is methamphetamine so dangerous societally? Why is methamphetamine so dangerous societally? It is the second most abused drug in the world and produces large amounts of violence and criminality It is the second most abused drug in the world and produces large amounts of violence and criminality Is the rush different from the cocaine rush? Is the rush different from the cocaine rush? The “rush” is almost identical, but lasts much longer. The “rush” is almost identical, but lasts much longer. In what ways does methamphetamine affect neurotransmitter levels in the synapse? 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. 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.

75 Crystal Describe tolerance and dependence with methamphetamine. Describe tolerance and dependence with methamphetamine. Tolerance is greater than with cocaine, strong behavioral dependence is mixed with physical dependence. 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? 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. 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? What is kind of unique about methamphetamine regarding serotonin? Meth users have depleted serotonin neurons, neurotoxicity, and hyperstupidity Meth users have depleted serotonin neurons, neurotoxicity, and hyperstupidity Describe the typical meth head. Describe the typical meth head. Patients often present as thin, hyperactive, paranoid, with CV effects, bruxism (teeth grinding), and ultra-bad teeth Patients often present as thin, hyperactive, paranoid, with CV effects, bruxism (teeth grinding), and ultra-bad teeth

76 Smoking!!!! Hooray!!!!! What percentage of deaths are related to smoking? Cancer cases? 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. 20% of deaths are related to smoking, 20% of new cancers are related to smoking. What percentage of smokers die from smoking? What percentage of smokers die from smoking? 1 of 2 smokers die from smoking 1 of 2 smokers die from smoking Describe the withdrawal syndrome from nicotine. Describe the withdrawal syndrome from nicotine. Anxiety, irritability, restlessness, difficulty concentrating, hunger, weight gain, insomnia, dysphoria Anxiety, irritability, restlessness, difficulty concentrating, hunger, weight gain, insomnia, dysphoria Symptoms last 1-2 weeks, cravings can last much longer/indefinitely Symptoms last 1-2 weeks, cravings can last much longer/indefinitely What are the three main disease processes with smoking? What are the three main disease processes with smoking? Cancer, heart disease, and chronic lung disease Cancer, heart disease, and chronic lung disease Of the many toxic chemicals in cigarette smoke, which are the most potent carcinogens? Of the many toxic chemicals in cigarette smoke, which are the most potent carcinogens? Aromatic amines, nitrosamines, and polyaromatic hydrocarbons Aromatic amines, nitrosamines, and polyaromatic hydrocarbons

77 Smoking Pathogenesis What is the chief metabolic product of nicotine? What molecule is a good indication of recent smoking? What is the chief metabolic product of nicotine? What molecule is a good indication of recent smoking? Cotinine Cotinine Carboxyhemoglobin Carboxyhemoglobin Does nicotine cause cancer? Does nicotine cause cancer? no no What is the mechanism of smoking induced cardiovascular disease? What 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. Carbon monoxide decreases oxygen delivery to tissues. Nicotine activates sympathetic system (release of catechol amines) and causes glucose intolerance. Oxidant gases play a role.

78 COPD and Quitting What is the mechanism of smoking-induced COPD? 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). 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? 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. It is useful in motivated patients, particularly for the early withdrawal stage of quitting. Medication aproximately doubles the quit rate achievable with counseling alone.

79 CNS Stimulants: Theapuetic Uses and Toxicity February 07, 2008 Galen R. Wenger

80 Chemical Convulsants What are the chemical convulsants? What are the chemical convulsants? Strychnine (common AR rodenticide), picrotoxin, and pentylenetetrazol Strychnine (common AR rodenticide), picrotoxin, and pentylenetetrazol What is the mechanism of stychnine? Of picrotoxin and pentylenetetrazol? What is the mechanism of stychnine? Of picrotoxin and pentylenetetrazol? Blocks postsynaptic inhibition of glycine in the spinal cord. 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 GABA A receptor. 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 GABA A receptor. For what were chemical convulsants previously used? 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. 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? What is pentylenetetrazol currently used for? Diagnosis of seizure disordes (fun!) Diagnosis of seizure disordes (fun!)

81 Strychnine poisoning What kind of seizure does strychnine poisoning cause? What kind of seizure does strychnine poisoning cause? Opisthotonic seizure (shown to the right) Opisthotonic seizure (shown to the right) How are these seizures and strychnine poisoning treated? How are these seizures and strychnine poisoning treated? IV diazepam, dark quiet room, activated charcoal if drug is still in GI tract. IV diazepam, dark quiet room, activated charcoal if drug is still in GI tract.

82 Methylxanthines What are the two methylxanthines (that we covered)? What are the two methylxanthines (that we covered)? Caffeine and theophylline (both are present in tea, by the way) 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? What are the CNS effects of mg of caffeine? The cardiovascular system? The musculature? Stimulation of CNS and medullary respiratory centers. Stimulation of CNS and medullary respiratory centers. Decrease in rate at low dose, tachycardia and increased CO at higher dose Decrease in rate at low dose, tachycardia and increased CO at higher dose Constricts the vasculature of the CNS Constricts the vasculature of the CNS Increased capacity for work with performance enhancing effects Increased capacity for work with performance enhancing effects How does caffeine increase urine output? How does caffeine increase urine output? The mechanism is unclear, increased CO with some change in kidney function (urine composition similar to thiazide diuretic use) The mechanism is unclear, increased CO with some change in kidney function (urine composition similar to thiazide diuretic use)

83 Mechanism and Kinetics What is the currently accepted mechanism of methylxanthines? What is the currently accepted mechanism of methylxanthines? Antagonism of adenosine is probably responsible for most of these drugs’ effects. 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. 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? What is the half life of methylxanthines? What percentage is metabolized before excretion? 3-7 hours in adults (Caffeine) 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) 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% >90%

84 Toxicity and Dependence What toxicities are noticed with high doses of methylxanthines? What toxicities are noticed with high doses of methylxanthines? Nervousness, insomnia, delirium, convulsions (not usually fatal) Nervousness, insomnia, delirium, convulsions (not usually fatal) Is caffeine mutagenic or teratogenic? Is caffeine mutagenic or teratogenic? Maybe, it does cause little mutated plant babies. Maybe, it does cause little mutated plant babies. Copout answer—“advise pregnant women to use caution and moderation” Copout answer—“advise pregnant women to use caution and moderation” Define physical dependence (again). Define physical dependence (again). Upon abrupt discontinuation of a drug, physical withdrawal symptoms occur. Upon abrupt discontinuation of a drug, physical withdrawal symptoms occur.

85 Amphetamines What are the amphetamine class psychomotor stimulants (4)? What are the amphetamine class psychomotor stimulants (4)? Amphetamine, methamphetamine, methylphenidate, phentermine Amphetamine, methamphetamine, methylphenidate, phentermine What effects do these drugs have in the periphery? What effects do these drugs have in the periphery? At low doses, methamphetamine has no peripheral effects. At low doses, methamphetamine has no peripheral effects. Others do. Others do. Rank their potency in the CNS. Rank their potency in the CNS. Methamphetamine > d-amphetamine > L-amphetamine & methylphenidate Methamphetamine > d-amphetamine > L-amphetamine & methylphenidate What are the primary CNS effects of amphetamines? What are the primary CNS effects of amphetamines? Stimulate medullary respiratory center, increase motor activity, elevate mood, insomnia, decrease fatigue Stimulate medullary respiratory center, increase motor activity, elevate mood, insomnia, decrease fatigue

86 Mechanism and Use What is the mechanism of amphetamines? 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. 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? What is the now abandoned therapeutic use of amphetamines? Weight control by effect on appetite (lasts about two weeks) Weight control by effect on appetite (lasts about two weeks) Now considered unethical Now considered unethical What are the current uses of amphetamines? What are the current uses of amphetamines? Attention Deficit Hyperactivity Disorder Attention Deficit Hyperactivity Disorder Hyperkinetic syndrome / ADHD, a paradoxical effect Hyperkinetic syndrome / ADHD, a paradoxical effect Methylphenidate and d-amphetamine have similar efficacy Methylphenidate and d-amphetamine have similar efficacy Narcolepsy Narcolepsy

87 Tolerance and Toxicity Describe the physical dependence and withdrawal experienced with amphetamines. 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) 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? What are the adverse effects of amphetamines in children? What toxicities occur? In children, insomnia, abdominal pain, anorexia, weight loss, In children, insomnia, abdominal pain, anorexia, weight loss, Following high doses of amphetamines, a psuedo-psychotic syndrome develops: 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. Visual hallucinations predominante with some auditory hallucinations, paranoid thoughts, changes in affect, prounounced sympathetic effects.

88 The Alcohols Feb 08, 2008

89 Ethanol basics Is ethanol a unique drug? In what ways (3)? Is ethanol a unique drug? In what ways (3)? Why yes it is, thanks for asking. 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. 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? What kind of doses are needed to produce CNS effects? Humongenormous doses, around 1-3 grams/kg Humongenormous doses, around 1-3 grams/kg Minimal effect in man below 15 grams Minimal effect in man below 15 grams How many chronic alcoholics are there in the U.S.? How many chronic alcoholics are there in the U.S.? About 10 million, (used recreationally by 2/3 of U.S. population) About 10 million, (used recreationally by 2/3 of U.S. population) What is the mechanism of absorption of ethanol? 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. 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? Can the lungs absorb ethanol? Ethanol vapor is rapidly absorbed from the lung Ethanol vapor is rapidly absorbed from the lung In what body compartemnt is ethanol distributed? In 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. Ethanol is distributed into total body water and is absorbed into organs and tissues based on their blood supply.

90 Kinetics How is expired air used to measure blood alcohol content? 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 concentrations Ethanol in 2100mL of expired air is equal to ethanol present in 1mL of blood at a wide range of concentrations How is mg% related to g/dL How is mg% related to g/dL 100 mg% = 0.1 g/dL 100 mg% = 0.1 g/dL What are the two routes of ethanol metabolism What are the two routes of ethanol metabolism Alcohol dehydrogenase (90%) and P450 system (10%) Alcohol dehydrogenase (90%) and P450 system (10%) What is the rate limiting step in ethanol metabolism? 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. 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 production Both steps use NAD and result in NADH production What order kinetics does ethanol metabolism follow? What order kinetics does ethanol metabolism follow? Due to saturation of alcohol dehydrogenase, 0 order Due to saturation of alcohol dehydrogenase, 0 order 7-10 grams of ethanol per hour is metabolized 7-10 grams of ethanol per hour is metabolized What is the maximum amount of calories absorbed from alcohol per day? What is the maximum amount of calories absorbed from alcohol per day? calories per day calories per day

91 Tolerance, Mechanism, Mellanby See sylabus for dose dependent effects. See sylabus for dose dependent effects. What is the legal level of alcohol in blood in most states (including arkansas)? What is the legal level of alcohol in blood in most states (including arkansas)? 0.08 g/dL 0.08 g/dL What is the mechanism of action of ethanol? What 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. 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 structure Replaces water in protein cavities which affects protein structure What is the maximum tolerance to alcohol observed? What is responsible for the drug dispositional tolerance? What 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) 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) Induction of microsomal P450 system (as well as a pharmacodynamic tolerance) Is alcohol cross-tolerant to other CNS depressants? Is alcohol cross-tolerant to other CNS depressants? Yes Yes What is the Mellanby effect? What 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) 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)

92 Withdrawal of ethanol Does physical dependence occur? Describe it. Does physical dependence occur? Describe it. Yes, it’s a two part withdrawal syndrome Yes, it’s a two part withdrawal syndrome Peak effects occur at hours, withdrawal lasts 5-7 days. Withdrawal occurs in two phases: Peak effects occur at hours, withdrawal lasts 5-7 days. Withdrawal occurs in two phases: Phase 1- Phase 1- Hyperirritability, exaggerated reflexes, sleeplessness, tremor, muscular tension, cold sweaty skin, nausea, thirst Hyperirritability, exaggerated reflexes, sleeplessness, tremor, muscular tension, cold sweaty skin, nausea, thirst Phase 2- (Delirium Tremens) Phase 2- (Delirium Tremens) Severe hyperactivity with delirium, hallucinations, fever, profuse sweating, intense vasodilation, severe tachycardia, tonic-clonic seizures Severe hyperactivity with delirium, hallucinations, fever, profuse sweating, intense vasodilation, severe tachycardia, tonic-clonic seizures

93 Adverse Effects What are the two ways to treat withdrawal? 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) 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? 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 cirrhosis Induction of P450, fatty degeneration of the liver, can lead to cirrhosis Erosive gastritis Erosive gastritis Gynecomastia, testicular atrophy, interference with release of prolactin, growth hormone, and antidiuretic hormone Gynecomastia, testicular atrophy, interference with release of prolactin, growth hormone, and antidiuretic hormone Decreased release of ADH with increased fluid intake Decreased release of ADH with increased fluid intake

94 Toxicity Why don’t people usually drink enough ethanol to kill themselves? Why 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 themselves They usually lapse into a “coma” before they are able to drink enough ethanol to kill themselves What emergent condition can be misdiagnosed as ethanol intoxication? What emergent condition can be misdiagnosed as ethanol intoxication? Diabetic coma Diabetic coma Ethanol on breath does not make the diagnosis! Ethanol on breath does not make the diagnosis! How can one treat alcohol overdose? How can one treat alcohol overdose? Enhance elimination with gastric lavage or hemodialysis Enhance elimination with gastric lavage or hemodialysis Supportive care: keep him breathing and perfusing tissues, correct metabolic acidosis, decrease intracranial pressure (mannitol), prevent aspiration of vomitus. Supportive 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? What percent of chronic alcoholics have liver damage? Cirrhosis? 100% 100% 20% 20%

95 Chronic Alcoholism How do you treat wernicke korsakoff? How do you treat wernicke korsakoff? High dose thiamine High dose thiamine How common is fetal alcohol syndrome? What are its three primary features for diagnosis? How much maternal consumption of ethanol is needed for “definite risk”? How 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. 4-7 per 1,000 live births in U.S. Microcephaly, prenatal growth deficiency, short palpebral fissures Microcephaly, prenatal growth deficiency, short palpebral fissures Definite risk with intake above 3/oz per day Definite risk with intake above 3/oz per day What are the treatments of chronic alcohoism? What are the treatments of chronic alcohoism? Pharmacologic- disulfiram, naltrexone, SSRIs Pharmacologic- disulfiram, naltrexone, SSRIs 12 step program 12 step program

96 Disulfiram Who is disulfiram good for? How does it work? Who is disulfiram good for? How does it work? Highly motivated patients Highly motivated patients It inhibits aldehyde dehydrogenase, increasing levels of acetaldehyde (aldehyde syndrome created) It inhibits aldehyde dehydrogenase, increasing levels of acetaldehyde (aldehyde syndrome created) Feels like a myocardial infarction Feels like a myocardial infarction What are the uses of ethanol? What 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 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

97 Wood Alcohol What are the initial symptoms of methanol? What are the toxic symptoms? What is the cause of death in overdose? What 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, disinhibitin A mild drunk: euphoria, muscle weakness, disinhibitin Within 3-36 hours, a series of toxic symptoms including: N/V, headache, delirium, GI pain, back pain, cold clammy hands, hyperemic optic disks. Within 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, seizures Severe cases include a metabolic acidosis with an anion gap, fixed dilated pupils, retinal damage, bradycardia, coma, seizures Immediate cause of death is respiratory arrest Immediate cause of death is respiratory arrest What is responsible for the toxicity of methanol? What is responsible for the toxicity of methanol? The metabolism of methanol is to formaldehyde and formic acid. These metabolites produce toxicity and acidosis The metabolism of methanol is to formaldehyde and formic acid. These metabolites produce toxicity and acidosis How do you treat methanol poisoning? How do you treat methanol poisoning? Maintain airway, infusion sodium bicarbonate, administer large doses of ethanol (use up the aldehyde dehydrogenase) Maintain airway, infusion sodium bicarbonate, administer large doses of ethanol (use up the aldehyde dehydrogenase) Can use hemodialysis, emesis. Can use hemodialysis, emesis.

98 Cannabinoids and Hallucinogens W.D. Wessinger February 11, 2008

99 Marijuana What is marijuana? What is Hashish? What is marijuana? What is Hashish? Dried parts of the cannabis plant, usually leaves and flower heads that are used as a smoking mixture Dried parts of the cannabis plant, usually leaves and flower heads that are used as a smoking mixture Dried resinous exudates of the flowering tops Dried resinous exudates of the flowering tops What is the most abundant psychoactive agent in marijuana? What is the most abundant psychoactive agent in marijuana? Delta-9-tetrahydrocannabinal, which makes up % of the weight of marijuana. Delta-9-tetrahydrocannabinal, which makes up % of the weight of marijuana. Describe the effects 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. Euphoria, altered perceptions, impaired short term memory, impaired balance, decreased concentration/attention, 4-8 hour impairment post-euphoria.

100 Pharmacology of Marijuana What effects does marijuana have on the cardiovascular system? What effects does marijuana have on the cardiovascular system? Increases of bpm, pulse of 140 bpm can occur. Increases of bpm, pulse of 140 bpm can occur. Increased blood pressure while lying down but decreased while standing. Increased blood pressure while lying down but decreased while standing. Vasodilation of scleral and conjunctival vessels resuting in blood shot eyes. Vasodilation of scleral and conjunctival vessels resuting in blood shot eyes. What neurological effects occur with high doses of marijuana? What neurological effects occur with high doses of marijuana? Frank hallucinations, anxiety and panic replace euphoria, delusions, paranoid feelings Frank hallucinations, anxiety and panic replace euphoria, delusions, paranoid feelings Describe cannabinoid CB1 receptors. CB2 receptors. Describe 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. 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 tissues CB2 receptors are found in the periphery, mostly associated with immune tissues What is the endogenous ligand for these receptors? What is the endogenous ligand for these receptors? Anandamide, an arachidonic acid derivative Anandamide, an arachidonic acid derivative

101 Tolerance and Legality What are the long term problems with marijuana use? What are the long term problems with marijuana use? Memory and learning problems, anxiety and panic attacks, loss of judgment, drug testing, and jail. Memory and learning problems, anxiety and panic attacks, loss of judgment, drug testing, and jail. Dramatic tolerance is noted to all but which effects? Dramatic tolerance is noted to all but which effects? Cardiovascular effects Cardiovascular effects Is marijuana legal in medical settings? Explain. Is 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: 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 chemotherapy Anti emetic for cancer chemotherapy Appetite stimulant in AIDS wasting syndrome Appetite stimulant in AIDS wasting syndrome Other proposed uses include anticonvulsant, muscle spasm and decreasing intraocular pressure. Other proposed uses include anticonvulsant, muscle spasm and decreasing intraocular pressure.

102 Lysergic acid diethylamide Describe LSD (chemically). 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. 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. Chemically it is an indolealkylamine that is structurally similar to NE, dopamine and serotonin. How much LSD is required to produce an effect? How much LSD is required to produce an effect? micrograms can produce an effect micrograms can produce an effect. What is the most noteworthy effect produced by LSD? 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. Visual hallucinations that are elaborated from visual disturbances such as prolonged afterimages and an overlapping of present and past perceptions. Auditory hallucinations are rare Auditory hallucinations are rare What are the other effects of LSD? What are the other effects of LSD? Increased blood pressure, dilated pupils, piloerection, hyperreflexia, pyrexia Increased blood pressure, dilated pupils, piloerection, hyperreflexia, pyrexia What is the mechanism of LSD? What is the mechanism of LSD? Probably an agonist at 5-HT 2, though it probably also affects many other receptors Probably an agonist at 5-HT 2, though it probably also affects many other receptors Give the five dollar word for flashbacks? Give the five dollar word for flashbacks? Hallucinogen persisting perception disorder Hallucinogen persisting perception disorder Can LSD precipitate serious depression or prolonged shizophrenic episodes? Can LSD precipitate serious depression or prolonged shizophrenic episodes? yes yes

103 LSD Does tolerance occur with LSD? Does tolerance occur with LSD? Yes, it appears rapidly and goes away rapidly. Yes, it appears rapidly and goes away rapidly. Cross-tolerance to other hallucinogens like beta phenylethylamines and psilocybin. Cross-tolerance to other hallucinogens like beta phenylethylamines and psilocybin. Does dependence occur with LSD? Does dependence occur with LSD? No No What is LSD used for medically? What is LSD used for medically? LSD is a schedule I drug with no recognized medical uses. LSD is a schedule I drug with no recognized medical uses.

104 Peyote and X What is MDMA? What is MDMA? MethyleneDioxyMethAmphetamine, or ecstacy, is a beta phenylethylamine hallucinogen. It is the newest in this class and is the successor to MDA. 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? What is MDA? What are its effects? 3,4-methylenedioxyamphetamine is also known as mescaline and is the active component of the peyote cactus. 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 hallucinations It is a mild intoxicant producing euphoria without frank hallucinations What medical use did MDMA have in the 1970s? What 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. Psychotherapists used MDMA in the 70s to help patients talk about their feelings. Then they played techno music put glow- sticks in their mouths.

105 MDMA toxicity What is it called when MDMA users take additional doses every couple of hours? What is it called when MDMA users take additional doses every couple of hours? Stacking Stacking What effects does MDMA have? What effects does MDMA have? Mild hallucinogen and stimulant, euphoria, clarity of emotions and feeling of well being, hypersensitivity to touch, bruxism, increased body temperature Mild hallucinogen and stimulant, euphoria, clarity of emotions and feeling of well being, hypersensitivity to touch, bruxism, increased body temperature What are the symptoms of MDMA toxicity? What are the symptoms of MDMA toxicity? Increased pulse and BP, heat exhaustion, brain damage/neurotoxicity (decreased serotenergic functioning) Increased pulse and BP, heat exhaustion, brain damage/neurotoxicity (decreased serotenergic functioning) How much ecstacy is required to produce serotenergic damage? How much ecstacy is required to produce serotenergic damage? One dose is plenty to decrease serotenergic function. Cognitive deficits occur. 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? 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. 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 Benzodiazepines seem to be effective and are less dangerous

106 Dissociative Anesthetics What is the prototype dissociative anesthetic? What are the other dissociative 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 (PCP). I love its other names: angel dust, KW, rocket fuel, embalming fluid. Phencyclidine, ketamine, and (I guess) dextromethorphan. Phencyclidine, ketamine, and (I guess) dextromethorphan. Was phencyclidine ever used as a general animal anesthetic? What is phencyclidine’s schedule? Was phencyclidine ever used as a general animal anesthetic? What is phencyclidine’s schedule? No No Schedule II, though analogs and precursors are schedule I. Schedule II, though analogs and precursors are schedule I. What is Sherm’s? What is Sherm’s? A street drug consisting of marijuana cigarettes impregnanted with phencyclidine (“dipped in embalming fluid”) A street drug consisting of marijuana cigarettes impregnanted with phencyclidine (“dipped in embalming fluid”)

107 Special K and Cough Syrup What is ketamine used for medically? What schedule is ketamine? What is ketamine used for medically? What schedule is ketamine? Pediatrics, burn patients, and in veterinary medicine Pediatrics, burn patients, and in veterinary medicine Schedule II Schedule II What schedule is dextromethorphan? Where is it found? What 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. 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? 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. 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? Which dissociative anesthetic is the most potent? Phencyclidine is the most potent and long lasting (6-10 hours) Phencyclidine is the most potent and long lasting (6-10 hours)

108 Effects, Dependence, Overdose What are the effects of dissociative anesthetics? What are the effects of dissociative anesthetics? Euphoria/dysphoria, analgesia (reported as superhuman strength), motor incoordination, drunken ataxia, slurred speech, vertical nystagmus Euphoria/dysphoria, analgesia (reported as superhuman strength), motor incoordination, drunken ataxia, slurred speech, vertical nystagmus Hallucinations of both visual and auditory types: distortions of space, time, and body image, detachment from environment, dissociation (“out-of-body”) Hallucinations 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? Do tolerance or dependence occur with PCP? Yes, both have been noted in animals, including withdrawal syndromes. Yes, both have been noted in animals, including withdrawal syndromes. What psychiatric (mis)diagnosis is often given to abusers of PCP? What psychiatric (mis)diagnosis is often given to abusers of PCP? Schizophrenia Schizophrenia What are the symptoms of PCP overdose? What are the symptoms of PCP overdose? Agitation alternating with stupor Agitation alternating with stupor Increased BP, psychosis, myoclonus, seizures, trauma?, rhabdomyolysis  myoglobinuria  renal failure Increased BP, psychosis, myoclonus, seizures, trauma?, rhabdomyolysis  myoglobinuria  renal failure Motor seizures and respiratory depression. Motor seizures and respiratory depression.

109 Overdose How might one treat PCP overdose? How might one treat PCP overdose? Just give diazepam and wait, everything else (antipsychotics, urinary acidification, talking them down) is bad. Just give diazepam and wait, everything else (antipsychotics, urinary acidification, talking them down) is bad. And keep them from hurting themselves or others. And keep them from hurting themselves or others.

110 Brain Over Good Luck


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