Antipsychotic Antipsychotic Agents: 1Agents: 1stst GenerationGeneration

Early antipsychoticsEarly antipsychotics Name all of the prototype 1Name all of the prototype 1stst generation generation

antipsychotic agents (7)antipsychotic agents (7) Thioridazine, chlorpromazine, thiohixene, Thioridazine, chlorpromazine, thiohixene,

fluphenazine, loxapine, haloperidol, and molindonefluphenazine, loxapine, haloperidol, and molindone Which one is the aliphatic derivative? The Which one is the aliphatic derivative? The

piperidine derivative? The piperazine piperidine derivative? The piperazine derivative?derivative? ChlorpromazineChlorpromazine ThioridazineThioridazine FluphenazineFluphenazine

Which one is the thioxanthene? The Which one is the thioxanthene? The Butyrophenone? The dibenzoxazipine? The Butyrophenone? The dibenzoxazipine? The dihroindolone?dihroindolone? ThiohixeneThiohixene HaloperidolHaloperidol LoxapineLoxapine molindonemolindone

Indications and Effects Indications and Effects What are the clinical indications of the 1What are the clinical indications of the 1stst generation generation

“typical” antipsychotics?“typical” antipsychotics? Schizophrenic (or otherwise psychotic) patients, for antiemetic Schizophrenic (or otherwise psychotic) patients, for antiemetic

properties, and to stop hiccupsproperties, and to stop hiccups Which of the typical antipsychotics are most effective?Which of the typical antipsychotics are most effective?

They are all equally effectiveThey 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 The butyrophenones and piperazine derivatives are the most potent (haloperidol and fluphenazine)potent (haloperidol and fluphenazine)

The aliphatic and piperidines are the least potent The aliphatic and piperidines are the least potent (chlorpromazine and thioridazine)(chlorpromazine and thioridazine)

What receptor mediates the activity of these What receptor mediates the activity of these compounds?compounds? Activity occurs through antagonism at the D2 dopamine Activity occurs through antagonism at the D2 dopamine

receptorreceptor How do these drugs prevent nausea and emesis? How do these drugs prevent nausea and emesis?

Which drug is NOT anti-emetic?Which drug is NOT anti-emetic? The antiemetic properties of these drugs are mediated through The antiemetic properties of these drugs are mediated through

blocking D2 receptors in the emesis chemoreceptor trigger blocking D2 receptors in the emesis chemoreceptor trigger zonezone

Thioridazine has no significant anti-emetic activityThioridazine has no significant anti-emetic activity

GroupsGroups Among this drug class, how is potency of the drug Among this drug class, how is potency of the drug

correlated with degree of extrapyramidal correlated with degree of extrapyramidal symptoms?symptoms? Higher potency seems to correspond with higher levels Higher potency seems to correspond with higher levels

of extrapyramidal side effectsof extrapyramidal side effects What three other receptors are blocked by some of What three other receptors are blocked by some of

these drugs? What group (generally) has more of these drugs? What group (generally) has more of these effects?these effects? Some of the 1Some of the 1stst generation antipsychotics are also generation antipsychotics are also

effective blockers of alpha adrenergic receptors, effective blockers of alpha adrenergic receptors, muscarinic cholinergic receptors and histamine muscarinic cholinergic receptors and histamine receptors.receptors.

In general the lower potency antipsychotics have In general the lower potency antipsychotics have greater activity at these other receptor sitesgreater activity at these other receptor sites

Which drug (listed) is commonly used for Which drug (listed) is commonly used for intractable hiccups?intractable hiccups? chlorpromazinechlorpromazine

Mechanism and Mechanism and PharmacokineticsPharmacokinetics

Which of the brain’s dopamine systems is associated Which of the brain’s dopamine systems is associated with the antipsychotic effects of these agents? Which with the antipsychotic effects of these agents? Which dopamine system is affected to cause the dopamine system is affected to cause the extrapyramidal effects?extrapyramidal effects? Blocking dopamine receptors in the mesolimbic-mesocortical Blocking dopamine receptors in the mesolimbic-mesocortical

systems results in the antipsychotic activitysystems results in the antipsychotic activity Blocking dopamine receptors in the nigrostriatal system Blocking dopamine receptors in the nigrostriatal system

mediates the extrapyramidal effectsmediates the extrapyramidal effects Antipsychotic activity is mediated through which Antipsychotic activity is mediated through which

subtype of dopamine receptor?subtype of dopamine receptor? The D2 subtypeThe D2 subtype

Rate these drugs as a group on oral availability, first Rate these drugs as a group on oral availability, first pass effect, protein binding, and lipid solubility.pass effect, protein binding, and lipid solubility. Put simply, they have a lot of all of that except for oral Put simply, they have a lot of all of that except for oral

availability, which is poor with incomplete absorption. They availability, which is poor with incomplete absorption. They are pharmacokinetically crappyare 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)

Adverse Effects—Motor Adverse Effects—Motor What motor adverse effect is common with the 1What motor adverse effect is common with the 1stst

generation antipsychotics in the first 5 days? Describe generation antipsychotics in the first 5 days? Describe the syndrome. How is it treated?the syndrome. How is it treated? Acute dystoniaAcute dystonia

Spasms of face, neck, and backSpasms of face, neck, and back Treated with anticholinergicsTreated with anticholinergics

What motor adverse effect is common with the 1What motor adverse effect is common with the 1stst generation antipsychotics between days 5 and 60? generation antipsychotics between days 5 and 60? Describe the syndrome. How is it treated?Describe the syndrome. How is it treated? AkathisiaAkathisia

is a syndrome characterized by unpleasant sensations of "inner" is a syndrome characterized by unpleasant sensations of "inner" restlessness that manifests itself with an inability to sit still or restlessness that manifests itself with an inability to sit still or remain motionless, hence its origin ancient Greek remain motionless, hence its origin ancient Greek αα (a), (a), withoutwithout, , not +(káthisis), not +(káthisis), sittingsitting] –] –http://http://en.wikipedia.org/wiki/Akathisiaen.wikipedia.org/wiki/Akathisia

Treat by lowering the dose and/or administering anticholinergicsTreat by lowering the dose and/or administering anticholinergics What motor adverse effect is common with the 1What motor adverse effect is common with the 1stst

generation antipsychotics between days 5 and 30? generation antipsychotics between days 5 and 30? Describe the syndrome. How is it treated?Describe the syndrome. How is it treated? (drug induced) parkinsonism(drug induced) parkinsonism

Looks like parkinson’s diseaseLooks like parkinson’s disease Treat by lowering the dose and/or administering anticholinergicsTreat by lowering the dose and/or administering anticholinergics

Even more side effectsEven more side effects

Describe the perioral tremor and its Describe the perioral tremor and its treatment.treatment. The “rabbit syndrome” involves tremors around The “rabbit syndrome” involves tremors around

the nose and mouth and can occur months or years the nose and mouth and can occur months or years after beginning treatment with antipsychotics. It is after beginning treatment with antipsychotics. It is treated like the others, with lowering the dose treated like the others, with lowering the dose and/or anticholinergicsand/or anticholinergics

The secretion of which hormone is increased The secretion of which hormone is increased by 1by 1stst generation antipsychotics? Which two generation antipsychotics? Which two hormones are decreased?hormones are decreased? Hyperprolactinemia occurs with these drugsHyperprolactinemia occurs with these drugs Decreased gonadotropin and estrogen releaseDecreased gonadotropin and estrogen release

Do first generation antipsychotics cause edema or Do first generation antipsychotics cause edema or weight gain?weight gain? Yes, bothYes, both

Which anti-psychotics (potency) cause more sedation?Which anti-psychotics (potency) cause more sedation? The lower potency anti-psychotics cause more sedationThe lower potency anti-psychotics cause more sedation

Which 1Which 1stst generation antipsychotic is best to use in a generation antipsychotic is best to use in a patient with a history of seizures?patient with a history of seizures? In general, these drugs lower seizure threshold and should be In general, these drugs lower seizure threshold and should be

used carefully in patients with a history of seizures. used carefully in patients with a history of seizures. Fluphenazine is the best choice in these patients.Fluphenazine is the best choice in these patients.

What is neuroleptic malignant syndrome? What is its What is neuroleptic malignant syndrome? What is its mortality? How is it treated?mortality? How is it treated? A rare but life threatening condition which resembles a very A rare but life threatening condition which resembles a very

severe form of parkinsonism with catatonia, autonomic severe form of parkinsonism with catatonia, autonomic instability (BP, pulse, temp), stupor and possibly instability (BP, pulse, temp), stupor and possibly myoglobinemia.myoglobinemia.

Mortality is >10%Mortality is >10% Treatment includes discontinuing the antipsychotic and Treatment includes discontinuing the antipsychotic and

adminstering dantrolene, along with supportive careadminstering dantrolene, along with supportive care

Way more side effectsWay more side effects

More bad stuffMore bad stuff Which autonomic receptors are commonly blocked by Which autonomic receptors are commonly blocked by

antipsychotics?antipsychotics? These drugs can block both the alpha-adrenergic receptors and the These drugs can block both the alpha-adrenergic receptors and the

muscarinic receptors, causing a variety of problems including urinary muscarinic receptors, causing a variety of problems including urinary retention.retention.

What effects do first generation antipsychotics have on the What effects do first generation antipsychotics have on the skin?skin? They cause both a blue-gray skin discoleration and a photosenitivity They cause both a blue-gray skin discoleration and a photosenitivity

that resembles a severe sunburn.that resembles a severe sunburn. Name three drug interactions of 1Name three drug interactions of 1stst generation generation

antipsychotics.antipsychotics. They potentiate the effect of CNS depressants, opioids, and They potentiate the effect of CNS depressants, opioids, and

antihistaminesantihistamines They reduce the effectiveness of L-dopa in patients with parkinsonism They reduce the effectiveness of L-dopa in patients with parkinsonism

(antagonism)(antagonism) They have additive anticholinergic effects with tricyclic They have additive anticholinergic effects with tricyclic

antidepressantsantidepressants How does a physician choose between the various How does a physician choose between the various

antipsychotics in determining which drug to give a patient?antipsychotics in determining which drug to give a patient? The selection of an agent often depends upon the side effects and the The selection of an agent often depends upon the side effects and the

ability of the individual patient to tolerate themability of the individual patient to tolerate them

Atypical Atypical Antipsychotics Antipsychotics and Lithiumand Lithium

January 29, 2008January 29, 2008

““I’m so happy I’m so happy ‘‘cause today I found my friends, cause today I found my friends,

they’re in my head. they’re in my head. I’m so ugly, I’m so ugly,

that’s ok ‘cause so are you.” that’s ok ‘cause so are you.”

ClozapineClozapine For which patients is clozapine approved?For which patients is clozapine approved?

Clozapine is only approved in patients suffering from Clozapine is only approved in patients suffering from schizophrenia who are refractory to more traditional schizophrenia who are refractory to more traditional antipsychotics.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 What makes clozapine’s side effect profile superior to other antipsychotics? What pharmacologic difference other antipsychotics? What pharmacologic difference might account for this?might account for this? Clozapine does not produce severe extrapyramidal dysfunction Clozapine does not produce severe extrapyramidal dysfunction

nor hyperprolacinemianor hyperprolacinemia Clozapine has a relatively low affinity for D1 and D2 receptors Clozapine has a relatively low affinity for D1 and D2 receptors

and is more specific for D4and is more specific for D4 Also, chronic treatment does not result in an increase in the Also, chronic treatment does not result in an increase in the

number or sensitivity of dopamine receptorsnumber or sensitivity of dopamine receptors What non-dopamine systems are affected by What non-dopamine systems are affected by

clozapine?clozapine? Clozapine causes changes in alpha adrenergic and muscarinic Clozapine causes changes in alpha adrenergic and muscarinic

receptors, as well as blocking serotonin (5HT-2 rec) receptors.receptors, as well as blocking serotonin (5HT-2 rec) receptors.

Just a few side effectsJust a few side effects What is the half life of clozapine? Which patients get higher What is the half life of clozapine? Which patients get higher

plasma levels?plasma levels? Half life is 12 hoursHalf life is 12 hours Young, women who smoke get higher plasma levels than older, non-Young, women who smoke get higher plasma levels than older, non-

smoking men.smoking men. What are the most common side effects of clozapine? What are What are the most common side effects of clozapine? What are

the dose limiting side effects? What is the unique nighttime the dose limiting side effects? What is the unique nighttime clozapine side effect? What adverse effect delayed its approval clozapine side effect? What adverse effect delayed its approval in the USA?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 Clozapine also causes excess salivation and severe drooling on your

pillow at night time.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 What percentage of patients on clozapine develop new onset seizures?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 Any patients with any kind of bone marrow problem or leukopenia, or

who are taking anything else that may affect the bone marrow who are taking anything else that may affect the bone marrow (carbamazepine)(carbamazepine)

The other atypicalsThe other atypicals Name the four mixed antagonist atypical (2Name the four mixed antagonist atypical (2ndnd Generation) anti- Generation) anti-

psychotics.psychotics. risperidone (risperdal), olanzapine (zyprexa), quetiapine (seroquel), risperidone (risperdal), olanzapine (zyprexa), quetiapine (seroquel),

and ziprasidone (zeldox)and ziprasidone (zeldox) Brand names are listed parenthetically just because the BS people use them Brand names are listed parenthetically just because the BS people use them

some of the timesome of the time All of these drugs antagonize D2 dopamine receptors, but what All of these drugs antagonize D2 dopamine receptors, but what

else do each of these drugs do? What is the half life of each drugelse do each of these drugs do? What is the half life of each drug RisperidoneRisperidone

Binds D2, 5-HT2, alpha adrenergic and histaminic H1Binds D2, 5-HT2, alpha adrenergic and histaminic H1 20 hours (w/active metabolie20 hours (w/active metaboliepaliperidone)paliperidone)

OlanzapineOlanzapine 5-HT2, 5-HT3, 5-HT6, D1, D2, D4, H1, 5-HT2, 5-HT3, 5-HT6, D1, D2, D4, H1, αα-1, and muscarinic M1-1, and muscarinic M1 30 hours30 hours

QuetiapineQuetiapine Has a higher affinity for 5-HT2 than D2Has a higher affinity for 5-HT2 than D2 6 hours6 hours

ZiprasidoneZiprasidone D2, 5-HT2, H1D2, 5-HT2, H1 7 hours7 hours

How are these drugs absorbed orally?How are these drugs absorbed orally? wellwell

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)

Side effects for days Side effects for days What are the most common side effects of risperidone? What are What are the most common side effects of risperidone? What are

the initial side effects (elderly)?the initial side effects (elderly)? AstheniaAsthenia, insomnia, difficulty concentrating, insomnia, difficulty concentrating Orthostatic hypotension and reflex tachycardiaOrthostatic hypotension and reflex tachycardia

Of the atypical antipsychotics, which has the highest incidence of Of the atypical antipsychotics, which has the highest incidence of extrapyramidal effects? Which causes the most extrapyramidal effects? Which causes the most hyperprolactinemia?hyperprolactinemia? RisperidoneRisperidone Risperidone Risperidone

What are the main side effects of olanzapine?What are the main side effects of olanzapine? Postural hypotension, somnolence, constipation, weight gain, Postural hypotension, somnolence, constipation, weight gain,

diabetes, dizziness, sexual dysfunction, and akathisia (these are pretty diabetes, dizziness, sexual dysfunction, and akathisia (these are pretty much the normal atypical antipsychotic side effects)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 olanzapineClozapine 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 Which atypical antipsychotic causes the greatest elongation of the QT interval? What does this drug cause the least of?QT interval? What does this drug cause the least of? Ziprasidone (so don’t use it with other QT prolonging drugs or Ziprasidone (so don’t use it with other QT prolonging drugs or

arrhythmia pts.)arrhythmia pts.) Of the atypical antipsychotics, ziprasidone causes the least weight Of the atypical antipsychotics, ziprasidone causes the least weight

gain.gain.

AripiprazoleAripiprazole What drug causes marked decrease in the clearance of What drug causes marked decrease in the clearance of

quetiapine?quetiapine? PhenytoinPhenytoin

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 Risperidone and olanzapine have been shown to be at least as

effective as haloperidoleffective as haloperidol What is the prototype partial agonist antipsychotic?What is the prototype partial agonist antipsychotic?

AripiprazoleAripiprazole For what is aripiprazole useful?For what is aripiprazole useful?

Equally useful as haloperidol for antipsychosis, aripiprazole is also Equally useful as haloperidol for antipsychosis, aripiprazole is also useful in acute manic episodesuseful 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-Partial agonist at D2 and 5-HT1a receptors and antagonist at 5-

HT2a receptorsHT2a receptors Is a “dopamine system stabilizer” in that it maintains a medium Is a “dopamine system stabilizer” in that it maintains a medium

amount of D2 activationamount of D2 activation What is the half life of aripiprazole? In what patients can What is the half life of aripiprazole? In what patients can

this be longer?this be longer? 75 hours75 hours In patients with variation in the CYP 2D6 system, the half life can be In patients with variation in the CYP 2D6 system, the half life can be

146 hrs.146 hrs.

More aripiprazole and More aripiprazole and conclusionsconclusions

What are the side effects of aripiprazole?What are the side effects of aripiprazole? Anxiety, headache, nauseas and vomiting, constipation, insomnia and Anxiety, headache, nauseas and vomiting, constipation, insomnia and

somnolence, lightheadednesssomnolence, lightheadedness NoNo extrapyramidal effects, hyperprolactinemia, hyperlipidemia, extrapyramidal effects, hyperprolactinemia, hyperlipidemia,

hyperglycemia, or weight gainhyperglycemia, or weight gain Name three CYP 2D6 inhibitors. What should be done with Name three CYP 2D6 inhibitors. What should be done with

aripiprazole if coadministered with any of these drugs?aripiprazole if coadministered with any of these drugs? Fluoxetine, paroxetine, quinidineFluoxetine, paroxetine, quinidine The dose of aripiprazole should be reduced if coadministered with any The dose of aripiprazole should be reduced if coadministered with any

of the above 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 While it is effective in treating schizophrenia without causing extrapyramidal symptoms, weight gain, hyperprolactinemia, or extrapyramidal symptoms, weight gain, hyperprolactinemia, or hyperlipidemia, aripiprazole has not been on the market long enough hyperlipidemia, aripiprazole has not been on the market long enough to evaluate its long term safety.to evaluate its long term safety.

What are the differences between 1What are the differences between 1stst and 2 and 2ndnd Generation Generation antipsychotics?antipsychotics? They are roughly equally effective in treating psychosisThey are roughly equally effective in treating psychosis First generations have a higher incidence of extrapyramidal effects, First generations have a higher incidence of extrapyramidal effects,

while second generation have a higher incidence of weight gain, while second generation have a higher incidence of weight gain, hyperglycemia, and hyperlipidemiahyperglycemia, and hyperlipidemia

Second generation drugs are about 10x as expensiveSecond generation drugs are about 10x as expensive

Lithium CarbonateLithium Carbonate How long does it take for lithium carbonate to work? What How long does it take for lithium carbonate to work? What

percentage of patients get their mood stabilized?percentage of patients get their mood stabilized? 2-3 weeks2-3 weeks Normalizes the mood of 80% of patientsNormalizes the mood of 80% of patients

What do you do if a patient is suffering from “an acute manic What do you do if a patient is suffering from “an acute manic attack” currently?attack” currently? Use an antipsychotic first, then introduce lithium later as the patient Use an antipsychotic first, then introduce lithium later as the patient

becomes stabilized becomes stabilized The low therapeutic index and severe toxicity of lithium require a The low therapeutic index and severe toxicity of lithium require a

cooperative and stable patientcooperative and stable patient Can lithium be used in patients with recurrent depression Can lithium be used in patients with recurrent depression

without mania?without mania? According to this lecture yes, but it is much more dangerous than According to this lecture yes, but it is much more dangerous than

the SSRIs.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 Downregulation of second messangers IP3 and DAG is currently considered the best possibility.considered the best possibility.

Other hypotheses include effects on ion transport or on serotonin Other hypotheses include effects on ion transport or on serotonin and dopamine systems.and dopamine systems.

What is the half life of lithium?What is the half life of lithium? About 20 hoursAbout 20 hours

What is the therapeutic window of lithium?What is the therapeutic window of lithium? 0.9 to 1.4 mEq/L0.9 to 1.4 mEq/L

Lithium toxicitiesLithium toxicities At what dose of lithium is toxicity first noticed? What At what dose of lithium is toxicity first noticed? What

is the treatment for lithium toxicity?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 treatmentThere is no specific treatment

What three toxicity symptoms are diagnostic of What three toxicity symptoms are diagnostic of lithium toxicity? What other symptoms occur?lithium toxicity? What other symptoms occur? Coarse tremor, hyperreflexia, and slurred speechCoarse tremor, hyperreflexia, and slurred speech Vomiting, profuse diarrhea, arrhythmia, hypotension, ataxia, Vomiting, profuse diarrhea, arrhythmia, hypotension, ataxia,

mental confusion, cranial nerve and focal neurologic deficits, mental confusion, cranial nerve and focal neurologic deficits, coma, convulsions, deathcoma, convulsions, death

What side effects are common at therapeutic doses?What side effects are common at therapeutic doses? Nausea, diarrhea, drowsiness, hypothyroidism, polydipsia and Nausea, diarrhea, drowsiness, hypothyroidism, polydipsia and

polyuria, weight gain, cognitive blunting, birth defectspolyuria, weight gain, cognitive blunting, birth defects Is lithium secreted in breast milk?Is lithium secreted in breast milk?

YesYes In which patients should lithium be used “with In which patients should lithium be used “with

caution”?caution”? Patients needing a low sodium diet and those in the first Patients needing a low sodium diet and those in the first

trimester of pregnancytrimester of pregnancy

Other DrugsOther Drugs What are two alternative drugs for What are two alternative drugs for

bipolar disorder?bipolar disorder? Carbamazepine and valproic acidCarbamazepine 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 A controlled study in the VA system has

shown it to be ineffective.shown it to be ineffective. Why might you use valproic acid Why might you use valproic acid

(Depakote) instead of lithium?(Depakote) instead of lithium? It appears to be as effective as lithium in the It appears to be as effective as lithium in the

early weeks of treatment, it has fewer side early weeks of treatment, it has fewer side effects, and the dose can be titrated up effects, and the dose can be titrated up more quickly.more quickly. Long term efficacy has not been determined.Long term efficacy has not been determined.

DementiaDementia How many americans are affected by dementia?How many americans are affected by dementia?

4.5 million americans4.5 million americans 100 billion dollars annually100 billion dollars annually

What is dementia?What is dementia? An acquired persistent and progressive impairment in intellectual function, An acquired persistent and progressive impairment in intellectual function,

with compromise in at least one other cognitive domain (below) that with compromise in at least one other cognitive domain (below) that impairs daily living.impairs daily living.

Language, visuospatial, calculation, judgment, problem solvingLanguage, visuospatial, calculation, judgment, problem solving What are the three most common forms of dementia in order of most What are the three most common forms of dementia in order of most

to least?to least? Alzheimer’s (60-80%), vascular dementia, lewy body dementiaAlzheimer’s (60-80%), vascular dementia, lewy body dementia

What neurotransmitter deficiency is theorized to be critical in the What neurotransmitter deficiency is theorized to be critical in the genesis of alzheimer’s disease? Where is one place in the brain that is genesis of alzheimer’s disease? Where is one place in the brain that is particularly affected (loss of neurons)?particularly affected (loss of neurons)? AcetylcholineAcetylcholine 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, galantamineTacrine, donepezil, rivastigmine, galantamine

Name the NMDA receptor antagonist.Name the NMDA receptor antagonist. MemantineMemantine

Name all the Name all the otherother drugs that are FDA approved for the treatment of drugs that are FDA approved for the treatment of Alzheimer’s disease.Alzheimer’s disease. There are noneThere are none

Alzheimer’s DiseaseAlzheimer’s Disease What is the first clinical feature of Alzheimer’s?What is the first clinical feature of Alzheimer’s?

Impairment of short-term memoryImpairment of short-term memory Is a deficiency of acetylcholine critical in the genesis Is a deficiency of acetylcholine critical in the genesis

of the symptoms of alzheimer’s disease?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 Centrally acting, noncompetitive, reversible cholinesterase

inhibitorinhibitor Also blocks reuptake of dopamine, NE, and serotonin. Inhibits Also blocks reuptake of dopamine, NE, and serotonin. Inhibits

MAOMAO Blocks sodium and potassium channelsBlocks sodium and potassium channels Partial muscarinic agonistPartial muscarinic agonist

What is Tacrine’s half life?What is Tacrine’s half life? 2-3.5 hours2-3.5 hours

What is the most important adverse effect of Tacrine? What is the most important adverse effect of Tacrine? What adverse effects are common?What adverse effects are common? 50% of patients get hepatic toxicity50% of patients get hepatic toxicity SLUD- salivation, lacrimation, urination, defecationSLUD- salivation, lacrimation, urination, defecation Nausea, vomiting, diarrhea, headache, myalgia, ataxiaNausea, vomiting, diarrhea, headache, myalgia, ataxia

DonepezilDonepezil How does donepezil work?How does donepezil work?

Noncompetitive, reversible inhibitor of acetylcholinesteraseNoncompetitive, reversible inhibitor of acetylcholinesterase What is donepezil’s half life?What is donepezil’s half life?

70 hours70 hours Why is donepezil better than tacrine?Why is donepezil better than tacrine?

Donepezil does not cause hepatic toxicityDonepezil does not cause hepatic toxicity What type of inhibitor is rivastigmine?What type of inhibitor is rivastigmine?

It is a “carbamate” inhibitor of acetylcholinesteraseIt is a “carbamate” inhibitor of acetylcholinesterase It is thus metabolized by acetylcholine to a decarbamylated It is thus metabolized by acetylcholine to a decarbamylated

productproduct What are the adverse effects of rivastigmine?What are the adverse effects of rivastigmine?

Nausea, vomiting, diarrhea, abdominal pain, anorexia, Nausea, vomiting, diarrhea, abdominal pain, anorexia, weight lossweight loss

No hepatic toxicityNo hepatic toxicity

GalantamineGalantamine Use some crazy chemestry words and a flower to Use some crazy chemestry words and a flower to

describe Galantamine.describe Galantamine. It is a tertiary alkaloid and phenanthrene derivative It is a tertiary alkaloid and phenanthrene derivative

extracted from daffodial bulbsextracted from daffodial bulbs Describe the mechanism of Galantamine.Describe the mechanism of Galantamine.

Reversible, competitive inhibitor of central Reversible, competitive inhibitor of central acetylcholinesterase. 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 In this class, it’s the only one listed to cause bradycardia. Other side effects are typical for a AchEbradycardia. Other side effects are typical for a AchE

MemantineMemantine What patient population (severity of disease) are helped What patient population (severity of disease) are helped

by Memantine?by Memantine? Moderate to severe Alzheimer’s disease patients are helped by Moderate to severe Alzheimer’s disease patients are helped by

memantine.memantine. Describe the mechanism of memantine. Why does this Describe the mechanism of memantine. Why does this

help?help? Noncompetitive NMDA receptor antagonist. It is thought to Noncompetitive NMDA receptor antagonist. It is thought to

prevent NMDA calcium channel opening at high firing rates (but prevent NMDA calcium channel opening at high firing rates (but not at lower, normal rates)not at lower, normal rates)

Excess NMDA activity is thought to be toxic to neurons, and to play a Excess NMDA activity is thought to be toxic to neurons, and to play a role in dying neurons reaching out and hurting their neighbor role in dying neurons reaching out and hurting their neighbor neuronsneurons

What clinical benefit does memantine cause? What is its What clinical benefit does memantine cause? What is its half life and elimination mode?half life and elimination mode? Some reduced rate of cognitive deterioration (maybe)Some reduced rate of cognitive deterioration (maybe) 60-80 hours, excreted in urine.60-80 hours, excreted in urine.

Describe memantine’s side effects?Describe memantine’s side effects? Dizziness, headache, Dizziness, headache, constipationconstipation, hallucinations, confusion, hallucinations, confusion

Other stuffOther stuff Which of the vitamin, antioxidant, and ginko biloba Which of the vitamin, antioxidant, and ginko biloba

“medicines” have been shown to help with Alzheimer’s “medicines” have been shown to help with Alzheimer’s disease?disease? None of themNone of them

What molecule is the toxic end product of beta secretase What molecule is the toxic end product of beta secretase and gamma secretase cleavage of APP?and gamma secretase cleavage of APP? AAββ--4242

Do we have any useful inhibitors of beta secretase or Do we have any useful inhibitors of beta secretase or gamma secretase?gamma secretase? NopeNope

Do antibodies to ADo antibodies to Aββ induce clerance of the molecule? induce clerance of the molecule? What bad thing happened in the (human) clinical study?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 patientsCaused meningoencephalitis in 6% of patients

How awesome is Etanercept?How awesome is Etanercept? Super awesomeSuper awesome

Pharmacologic Pharmacologic Management of Management of

Parkinsonism and Parkinsonism and Huntington’sHuntington’s

Parkinsonian basicsParkinsonian basics In parkinson’s, symptoms start ______ and become _____.In parkinson’s, symptoms start ______ and become _____.

Unilateral, bilateralUnilateral, 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), Tremor (pill rolling, non-intention), rigidity (cogwheel), bradykinesia/akinesiabradykinesia/akinesia

What percent of adults over age 65 will get parkinson’s What percent of adults over age 65 will get parkinson’s (idiopathic)?(idiopathic)? About 1 percentAbout 1 percent

What drugs cause drug-induced parkinsonism?What drugs cause drug-induced parkinsonism? MPTP, antipsychotic medicationsMPTP, 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 typically inhibits ACh excititory neurons, decreased

dopamine causes an imbalance in this system.dopamine causes an imbalance in this system. This is the rationale for the use of anticholinergic agents like ____ This is the rationale for the use of anticholinergic agents like ____

and ____.and ____. trihexyphenidyl and benzotropinetrihexyphenidyl and benzotropine

Stages and TypesStages and Types What are the stages of parkinson’s disease?What are the stages of parkinson’s disease?

1.1. Unilateral symptoms, tremor of one upper limb, slight Unilateral symptoms, tremor of one upper limb, slight lateral tilt of upper body away from affected side, lateral tilt of upper body away from affected side, reduced arm swing, cogwheel.reduced arm swing, cogwheel.

2.2. Bilateral symptoms, stooped posture, more apparent Bilateral symptoms, stooped posture, more apparent motor symptomsmotor symptoms

3.3. Shuffling gate becomes severe (falls)Shuffling gate becomes severe (falls)4.4. And 5. continual decline in functionAnd 5. continual decline in function

– What are the four types of parkinsonism?What are the four types of parkinsonism?– Postencephalitic parkinson’sPostencephalitic parkinson’s IdiopathicIdiopathic– Drug inducedDrug induced– Miscellaneous (??)Miscellaneous (??)

MedicationsMedications What were the first drugs used against parkinsonism?What were the first drugs used against parkinsonism?

AnticholinergicsAnticholinergics 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-Anticholinergics are used for psychotic patients (who shouldn’t take L-dopa) and for drug induced parkinsonism. They are also used in dopa) and for drug induced parkinsonism. They are also used in combination with L-dopa in some patients.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 slowlyBy 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, deliriumChoreiform movements, mental confusion, delirium

N & V, orthostatic hypotension, arrhythmias also occurN & V, orthostatic hypotension, arrhythmias also occur N & V or N/V is nausea and vomitingN & V or N/V is nausea and vomiting

What drug interactions with L-dopa are problematic? Which one is What drug interactions with L-dopa are problematic? Which one is useful?useful?

MAOinhibitors (hypertensive crisis) and antipsychotics (antagonism) are MAOinhibitors (hypertensive crisis) and antipsychotics (antagonism) are contraindicated, pyridoxine (B6) causes rapid metabolism of L-dopa.contraindicated, pyridoxine (B6) causes rapid metabolism of L-dopa.

Carbidopa coadministration increases the percentage of L-dopa that Carbidopa coadministration increases the percentage of L-dopa that crosses the BBB, reducing the necessary dose of L-dopa 7-10 fold.crosses the BBB, reducing the necessary dose of L-dopa 7-10 fold.

ErgotsErgots How well does amantadine work for parkinsonism? What is it normally used for? How well does amantadine work for parkinsonism? What is it normally used for?

What are its side effects.What are its side effects. Only useful for a couple of weeksOnly useful for a couple of weeks Amantadine is an antiviral agent that also causes release of dopamine from dopamine 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)neurons and has a little NMDA antagonism (half life 2-4 hours) Headache, confusion, and hallucinationsHeadache, confusion, and hallucinations

What is the mechanism of Bromocriptine and Pergolide? What is the difference in What is the mechanism of Bromocriptine and Pergolide? What is the difference in their mechanisms?their mechanisms?

These drugs are These drugs are direct acting dopamine agonistsdirect acting dopamine agonists Bromocriptine is an agonist at D2 but an antagonist at D1, pergolide is an agonist at D1 Bromocriptine is an agonist at D2 but an antagonist at D1, pergolide is an agonist at D1

and 2.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 + carbidopaBromocriptine 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 thatIt 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 Raynaud like digital spasms, abnormal choreiform movements, dyskinesias, mental

confusion, delirium, hallucinations, and depression, postural hypotension, premature confusion, delirium, hallucinations, and depression, postural hypotension, premature atrial contractions, sinus tachycardia, and angina. Also nausea and vomiting. Sounds atrial contractions, sinus tachycardia, and angina. Also nausea and vomiting. Sounds fun.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, History of psychotic illness, recent myocardial infarction, peripheral vascular disease,

and peptic ulcersand peptic ulcers Cost- it is very expensiveCost- it is very expensive

What are the newer dopamine agonists?What are the newer dopamine agonists? Pramipexole and ropinirolePramipexole and ropinirole

Why are these better than the ergot derivatives?Why are these better than the ergot derivatives? They are better toleratedThey are better tolerated

What strange effect sometimes happens with What strange effect sometimes happens with these new dopamine agonists?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 MAOIt inhibits the B form of MAO The drug leaves the A form of MAO alone, which The drug leaves the A form of MAO alone, which

prevents the problem of hypertensive crisisprevents the problem of hypertensive crisis Also some studies indicate that these drugs actually Also some studies indicate that these drugs actually

reverse some of the damage in parkinson’s diseasereverse some of the damage in parkinson’s disease

Yo-yo-yoing holidaysYo-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 EntacaponeTolcapone 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 They are used as adjuvant therapy to increase the “on time” of the L-dopa (in patients with “wearing off”)(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 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 hours, thought to be caused by decreased central conversion to dopamine and decreased dopamine storage.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 Obviously, the easy way (for the doc) is to just make the patient take the

medicine every three hours (at half the dose).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. Abnormal, involuntary movements which occur 1-2 hours after dosing. May involve excess dopamine)May involve excess dopamine)

Smaller and more frequent dosesSmaller 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 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 poorly. This effect is not understood and is not related to dosing frequency or size.frequency or size.

Thought to be caused during a point where disease process is almost too Thought to be caused during a point where disease process is almost too severe to be relieved by drugs anymore.severe to be relieved by drugs anymore.

How useful are drug holidays?How useful are drug holidays? Not shown to be helpfulNot shown to be helpful

Huntington’s ChoreaHuntington’s Chorea How many people get Huntington’s? At what age?How many people get Huntington’s? At what age?

1/50,0001/50,000 Age 37-47 yearsAge 37-47 years

What are the early symptoms of Huntingtons?What are the early symptoms of Huntingtons? catatoniacatatonia, aggressive outbursts, psychotic behavior, , aggressive outbursts, psychotic behavior,

exaggerated reflexes, good muscle strength, but weak toneexaggerated reflexes, good muscle strength, but weak tone What are the later symptoms?What are the later symptoms?

Progressively worsening dementia, increased appetite without Progressively worsening dementia, increased appetite without weight gainweight gain

What are the final stage symptoms?What are the final stage symptoms? Greatly increased diet with weight loss, rigid motor tone, Greatly increased diet with weight loss, rigid motor tone,

death within 10-15 years of onset of symptomsdeath within 10-15 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 antipsychoticsReserpine, phenothiazine and butyrophenone antipsychotics What drugs make the motor symptoms worse?What drugs make the motor symptoms worse?

L-dopa, anticholinergics, and dopamine agonistsL-dopa, anticholinergics, and dopamine agonists

Non-steroidal Non-steroidal Anti-Anti-

inflammatory inflammatory DrugsDrugsFebruary 4, 2008February 4, 2008

What is the mechanism of the NSAIDs?What is the mechanism of the NSAIDs? They all inhibit cyclooxygenase and subsequent They all inhibit cyclooxygenase and subsequent

prostaglandin and thromboxane synthesis.prostaglandin and thromboxane synthesis. They do not inhibit the leukotriene pathway. Shunting They do not inhibit the leukotriene pathway. Shunting

of arachidonic acid to the leukotriene pathway has of arachidonic acid to the leukotriene pathway has been hypothesized as a mechanism of toxicity and been hypothesized as a mechanism of toxicity and anaphylaxis.anaphylaxis.

What’s the difference between COX-1 and 2What’s the difference between COX-1 and 2 Cox 2 is an inducible form, whereas Cox-1 is present in Cox 2 is an inducible form, whereas Cox-1 is present in

every cell. Major sites of Cox-1 that result in toxicity every cell. Major sites of Cox-1 that result in toxicity are:are:

Platelets, blood vessles, stomach, kidneyPlatelets, blood vessles, stomach, kidney Theoretically, why are COX-2 inhibitors better Theoretically, why are COX-2 inhibitors better

than regular NSAIDs?than regular NSAIDs? They don’t cause problems in places listed above.They don’t cause problems in places listed above.

What effect do prostaglandins have on pain?What effect do prostaglandins have on pain? Prostaglandins decrease pain thresholdProstaglandins 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, Effective against mild to moderate and dull aching pain,

though they can be as effective as opiates in certain types though they can be as effective as opiates in certain types of painof pain

In jaw and mouth surgery NSAIDs are just as effective as In jaw and mouth surgery NSAIDs are just as effective as opiatesopiates

How do NSAIDs cause anti-inflammatory effects?How do NSAIDs cause anti-inflammatory effects? Inhibiting PGE2 and PGI2 reduces edema formationInhibiting PGE2 and PGI2 reduces edema formation At high concentrations NSAIDs reduce neutrophil At high concentrations NSAIDs reduce neutrophil

migrationmigration What mediates NSAIDs antipyretic effect?What mediates NSAIDs antipyretic effect?

NSAIDs prevent PGE2 formation, which is believed to be NSAIDs prevent PGE2 formation, which is believed to be responsible for altering the body temperature set pointresponsible for altering the body temperature set point

Side effectsSide effects What are NSAIDs used for?What are NSAIDs used for?

Pain, primary dysmenorrhea, joint inflammation (side effects are a Pain, primary dysmenorrhea, joint inflammation (side effects are a problem when used for inflammation in rheumatism), fever, sunburnproblem 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 dosesAspirin in high doses

What are the most common side effects of the NSAIDs? What What are the most common side effects of the NSAIDs? What causes these problems?causes these problems? GI distress, damge, bleeding/ulcerationGI distress, damge, bleeding/ulceration Prostaglandins PGE2 and PGI2 decrease acid secretion and increase Prostaglandins PGE2 and PGI2 decrease acid secretion and increase

mucous production. NSAIDS decrease the formation of these mucous production. NSAIDS decrease the formation of these prostaglandins and increase the likelihood of GI problems. Chronic prostaglandins and increase the likelihood of GI problems. Chronic use results in erosion of the stomach lininguse 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 PGI2 and PGE2 cause vasodilation of the afferent arteriole, which

promotes GFR. NSAIDs decrease production of these chemicals and promotes GFR. NSAIDs decrease production of these chemicals and decrease GFR.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 TXA2 makes platelets “sticky,” and is a potent vasoconstrictor

(procoagulant). Epithelial cells produce PGI2 in response to platelet (procoagulant). Epithelial cells produce PGI2 in response to platelet activity, which inhibits platelet aggregation. NSAIDs inhibit platelet activity, which inhibits platelet aggregation. NSAIDs inhibit platelet TXA2 and PGI2 production, which can cause a net increased bleeding TXA2 and PGI2 production, which can cause a net increased bleeding time.time.

SalicylateSalicylate What is the prototype Salicylate? How does it work?What is the prototype Salicylate? How does it work?

AspirinAspirin It is an irreversible inhibitor of prostaglandin synthesis It is an irreversible inhibitor of prostaglandin synthesis

(binds COX nonselectively and irreversibly)(binds COX nonselectively and irreversibly) What is special about aspirin’s nonreversible What is special about aspirin’s nonreversible

mechanism?mechanism? Since aspirin binds COX irreversibly, it permanently Since aspirin binds COX irreversibly, it permanently

reduces a platelet’s ability to aggregate. It’s effects on reduces a platelet’s ability to aggregate. It’s effects on epithelial cells are minimal, however, as epithelial cells epithelial cells are minimal, however, as epithelial cells can make new COX.can make new COX.

What is aspirin metabolized to? How long is aspirin’s What is aspirin metabolized to? How long is aspirin’s half life? What kinetics does aspirin follow?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 dosesFirst 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 Decreased pH increases unionized drug available for

distribution. Aspirin makes the blood more acidic.distribution. Aspirin makes the blood more acidic.

Aspirin toxicitiesAspirin toxicities What aspirin toxicity is common at higher therapeutic What aspirin toxicity is common at higher therapeutic

doses (2-4 g)? mild toxicity at 6-8g? Moderate toxcity at 8-doses (2-4 g)? mild toxicity at 6-8g? Moderate toxcity at 8-10 g? Severe intoxication at 20-50 g?10 g? Severe intoxication at 20-50 g? Bleeding, decreased uric acid excretion, hypersensitivity reactionsBleeding, decreased uric acid excretion, hypersensitivity reactions Salicylism, tinnitus (early warning sign), increased metabolic rate Salicylism, tinnitus (early warning sign), increased metabolic rate

(uncoupled mitochondria) with consequent fever, hyperventilation (uncoupled mitochondria) with consequent fever, hyperventilation and respiratory alkalosisand respiratory alkalosis

Moderate toxicity causes respiratory depression with respiratory, Moderate toxicity causes respiratory depression with respiratory, chemical, and metabolic acidosis (which is exacerbated by the chemical, and metabolic acidosis (which is exacerbated by the previous alkalosis).previous alkalosis).

Severe toxicity involves wild pH, hyperthermia, dehydration, loss Severe toxicity involves wild pH, hyperthermia, dehydration, loss of electrolytes, and is life threatening (coma, renal and respiratory of electrolytes, and is life threatening (coma, renal and respiratory failure).failure).

How does one treat salicylate intoxication?How does one treat salicylate intoxication? Cool, rehydrate, correct acid base and electrolyte imbalanceCool, rehydrate, correct acid base and electrolyte imbalance Prevent further absorption (emesis/lavage)Prevent further absorption (emesis/lavage) Alkalinize the urine to increase excretionAlkalinize the urine to increase excretion HemodialysisHemodialysis Diazepam for convulsionsDiazepam for convulsions

NSAID varietiesNSAID varieties For whom is aspirin contraindicated?For whom is aspirin contraindicated?

Patients with: renal disease, bleeding disorders, hypersensitivity, gout, Patients with: renal disease, bleeding disorders, hypersensitivity, gout, and young children during or following a viral infectionand young children during or following a viral infection

Is ibuprofen another NSAID? How effective of an analgesic is it? Is ibuprofen another NSAID? How effective of an analgesic is it? Of an anti-inflammatory? What are ibuprofen’s side effects?Of an anti-inflammatory? What are ibuprofen’s side effects? YesYes At low dose, it is more effective than aspirin at analgesiaAt low dose, it is more effective than aspirin at analgesia At high doses, its anti-inflammatory action is just as good as aspirinAt high doses, its anti-inflammatory action is just as good as aspirin GI irritation and bleeding, rash, tinnitus w/dizziness, agranulocytosis, GI irritation and bleeding, rash, tinnitus w/dizziness, agranulocytosis,

aplastic anemia, renal failure, interstitial nephritis, nephrotic aplastic anemia, renal failure, interstitial nephritis, nephrotic syndrome.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 (<ibuprofen or aspirin)Intermediate potency (<ibuprofen or aspirin) Has increased incidence of side effects (GI pain most common) Has increased incidence of side effects (GI pain most common)

compared to ibuprofen, likely due to need for increased dosecompared to ibuprofen, likely due to need for increased dose What is the most potent NSAID? What is it used for? What are its What is the most potent NSAID? What is it used for? What are its

major toxicities? Half life?major toxicities? Half life? IndomethacinIndomethacin Used for acute gout, spondylitis, osteoarthritis, and is the drug of Used for acute gout, spondylitis, osteoarthritis, and is the drug of

choice to close a patent ductus arteriosischoice to close a patent ductus arteriosis High incidence of GI distress and other toxicities (25% of patients will High incidence of GI distress and other toxicities (25% of patients will

discontinue)discontinue) 4-5 hours4-5 hours

What is ketoralac used for?What is ketoralac used for? Ketoralac is the only IV NSAID. It is used for short Ketoralac is the only IV NSAID. It is used for short

term pain managemement, can be used to replace term pain managemement, can be used to replace morphine in certain conditions but is often used with morphine in certain conditions but is often used with an opiate an opiate

What are COX-2 inhibitors used for?What are COX-2 inhibitors used for? RA, OA, acute pain, dysmenorrheaRA, 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 They are prothrombotic, and in clinical trials they have

been shown to cause a 2-4 fold increase in the been shown to cause a 2-4 fold increase in the incidence of cardiovascular side effectsincidence of cardiovascular side effects

It is suspected that selective COX-2 inhibitors have selective It is suspected that selective COX-2 inhibitors have selective inhibitor activity against prostacyclin (PGI2) synthase (as inhibitor activity against prostacyclin (PGI2) synthase (as opposed to TXA2). This makes them prothrombotic.opposed to TXA2). This makes them prothrombotic.

What is Meloxicam?What is Meloxicam? It is a It is a partiallypartially selective COX-2 inhibitor with a 20 selective COX-2 inhibitor with a 20

hour half lifehour half life

What is gout?What is gout? Gout is a metabolic disorder characterized by hyperuricemia and Gout is a metabolic disorder characterized by hyperuricemia and

deposition of monosdium urate in the tissues, particularly in the deposition of monosdium urate in the tissues, particularly in the joints. Inflammation is triggered by the actions of the infiltrated joints. Inflammation is triggered by the actions of the infiltrated granulocytes.granulocytes.

Granulocytes release lysosomal enzymes and inflammatory mediatorsGranulocytes release lysosomal enzymes and inflammatory mediators What is used for acute treatment of gout (2 drugs)? How What is used for acute treatment of gout (2 drugs)? How

does each work?does each work? CochicineCochicine

Inhibits release of chemotactic and inflammatory mediators, inhibiting Inhibits release of chemotactic and inflammatory mediators, inhibiting neutrophil activation. (highly toxic with low therapeutic index)neutrophil activation. (highly toxic with low therapeutic index)

IndomethacinIndomethacin Drug of choice to reduce inflammation. Why indomethacin?Drug of choice to reduce inflammation. Why indomethacin?

Others will inhibit uric acid excretionOthers 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 urateUrocusuric agents prevent renal tubular reabsorption of urate Probenecid and sulfinpyrazoneProbenecid and sulfinpyrazone

These drugs are not for patiets who already produce and excrete large amounts These drugs are not for patiets who already produce and excrete large amounts or urateor urate

Keep urine volume high and pH > 6Keep urine volume high and pH > 6 AllopurinolAllopurinol

Inhibits xanthine oxidase, blocks urate synthesisInhibits xanthine oxidase, blocks urate synthesis GI irritation and skin reactionsGI irritation and skin reactions

Management of Management of Acetominophen Acetominophen

overdoseoverdoseDr. Laura JamesDr. Laura James

What is the major cause of acute liver failure in the What is the major cause of acute liver failure in the United States today?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 Acetominophen is also one of the most common causes of pharmaceutical product poisoningpharmaceutical product poisoning

What is the most studied drug in toxicology?What is the most studied drug in toxicology? AcetominophenAcetominophen

How long does absorption take of a therapeutic dose? How long does absorption take of a therapeutic dose? Of an overdose?Of an overdose? A therapeutic dose is completely absorbed within 1 hour, but A therapeutic dose is completely absorbed within 1 hour, but

overdose can delay absorption up to 4 hoursoverdose can delay absorption up to 4 hours What order kinetics does acetominophen follow? What order kinetics does acetominophen follow?

What is the half life?What is the half life? It follows first order kinetics (exception in liver failure, 0 It follows first order kinetics (exception in liver failure, 0

order kinetics)order kinetics) 2.5 to 4 hours2.5 to 4 hours

What is the mechanism of acetominophen?What is the mechanism of acetominophen? Mechanism is somewhat unknown, some recent evidence Mechanism is somewhat unknown, some recent evidence

indicates a role in the central serotonin system. indicates a role in the central serotonin system. It is a weak inhibitor of cyclooxygenase, and as minimal It is a weak inhibitor of cyclooxygenase, and as minimal

antiinflammatory and neutrophil activation effects. antiinflammatory and neutrophil activation effects. What is good about acetominophen from a side effect What is good about acetominophen from a side effect

stand point?stand point? It is not a gastric irritant and has no effect on plateletsIt 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 acetominophenDescribe the metabolism of acetominophen At therapuetic doses >90 % undergoes glucuronidation and At therapuetic doses >90 % undergoes glucuronidation and

sulfation and is eliminated by the kidneyssulfation and is eliminated by the kidneys Small remainder is metabolized by CYP P450 to NAPQI, a toxic Small remainder is metabolized by CYP P450 to NAPQI, a toxic

metabolite. NAPQI is then detoxified by glutathione in non-metabolite. NAPQI is then detoxified by glutathione in non-overdose situations.overdose situations.

CYP 2E1 is the primary P450 system involved.CYP 2E1 is the primary P450 system involved.

Describe metabolism of Ac in overdose and the mechanism Describe metabolism of Ac in overdose and the mechanism of toxicity (4 steps).of toxicity (4 steps).

1.1. Normal pathways are overwhelemed, build up of NAPQI occursNormal pathways are overwhelemed, build up of NAPQI occurs2.2. Glutathione is depletedGlutathione is depleted3.3. NAPQI binds to proteins (hepatocytes), forming adducts.NAPQI binds to proteins (hepatocytes), forming adducts.4.4. Cell deathCell death

Agewise, who is more susceptible to acetominophen Agewise, who is more susceptible to acetominophen poisoning?poisoning?

Adults are more susceptible to acetominophen toxicity, whereas kids Adults are more susceptible to acetominophen toxicity, whereas kids seem to be “relatively protected”seem to be “relatively protected”

How does ethanol increase the risk of acetominophen How does ethanol increase the risk of acetominophen toxicity?toxicity?

Long term use of ethanol induces CYP 2E1 by 2-3 foldLong term use of ethanol induces CYP 2E1 by 2-3 fold Binge use of alcohol at the time of overdose may Binge use of alcohol at the time of overdose may decreasedecrease NAPQI NAPQI

formationformation What is a toxic dose of acetominophen in a child? In an What is a toxic dose of acetominophen in a child? In an

adult? Is this information on the test?adult? Is this information on the test? 150 mg/kg150 mg/kg 7.5 grams7.5 grams

Max Therapeutic dose is 90 mg/kg/day in a child or 4 grams per day for Max Therapeutic dose is 90 mg/kg/day in a child or 4 grams per day for adultadult

yesyes

Describe the four phases of acetominophen Describe the four phases of acetominophen toxicity.toxicity.

1.1. 0.5-24 hours0.5-24 hours1.1. Nausea, vomiting, elevation of hepatic transaminases, or Nausea, vomiting, elevation of hepatic transaminases, or

asymptomaticasymptomatic

2.2. 24-72 hours24-72 hours1.1. Abdominal tenderness in RUQ. Elevated hepatic enzymes. Abdominal tenderness in RUQ. Elevated hepatic enzymes.

Clotting factors impaired. May have renal involvement.Clotting factors impaired. May have renal involvement.

3.3. 72-96 hours72-96 hours1.1. Sequelae of hepatic injury: jaundice, coagulation defects, Sequelae of hepatic injury: jaundice, coagulation defects,

hepatic encephalopathy, renal failure, hepatic encephalopathy, renal failure, deathdeath will happen will happen in this phasein this phase1.1. Hard to get history at this point. If you show up to the hospital Hard to get history at this point. If you show up to the hospital

now, it is hard to treat you.now, it is hard to treat you.

4.4. 4-14 days4-14 days1.1. They get better and the liver fully recoversThey get better and the liver fully recovers

TreatmentTreatment What kind of liver damage is done by acetominophen What kind of liver damage is done by acetominophen

toxicity (a path. term)?toxicity (a path. term)? Centrilobular necrosisCentrilobular necrosis

Describe the treatment of acetominophen poisoning. Describe the treatment of acetominophen poisoning. Why is it important to treat quickly? What is the major Why is it important to treat quickly? What is the major adverse effect of this drug?adverse effect of this drug? N-acetylcysteine (NAC)N-acetylcysteine (NAC)

Works at the glutathione step as a glutathione substitute to prevent Works at the glutathione step as a glutathione substitute to prevent “adduct” formation“adduct” formation

IV NAC got approved in 2004IV NAC got approved in 2004 Efficacy is highly dependent on the time of NAC relative to Efficacy is highly dependent on the time of NAC relative to

the overdose. the overdose. Treatment within 10 hours –6% risk of toxicityTreatment within 10 hours –6% risk of toxicity 10-24 hours after overdose—26.4% risk of toxicity10-24 hours after overdose—26.4% risk of toxicity

Vomiting is the major side effect. Anaphylaxis is also a Vomiting is the major side effect. Anaphylaxis is also a possibility, especially with IV dosing.possibility, especially with IV dosing.

What treatments can be effective if administered What treatments can be effective if administered within two hours of the overdose?within two hours of the overdose? Activated charcoalActivated charcoal

Do you treat the patients nausea and vomiting?Do you treat the patients nausea and vomiting? yesyes

What is the maximum dose of What is the maximum dose of acetominophen for adults? For children?acetominophen for adults? For children? 4 grams/day adults or 90mg/kg/day in children4 grams/day adults or 90mg/kg/day in children

What percentage of acetominophen related What percentage of acetominophen related acute liver failure is caused by acute liver failure is caused by opiod/acetominophen mixes?opiod/acetominophen mixes? 50 %50 %

Should you remember the numbers from Should you remember the numbers from this lecture?this lecture? Oh yeah, big time. And remember/be able to Oh yeah, big time. And remember/be able to

use that graph.use that graph.

Opioid analgesics Opioid analgesics and antagonistsand antagonists

Paul L. Prather—Feb 05, Paul L. Prather—Feb 05, 20082008

What is the difference between an What is the difference between an opioid and an opiate?opioid and an opiate? Opioid is a general term for drugs that act Opioid is a general term for drugs that act

at opioid receptors, whereas opiates are at opioid receptors, whereas opiates are drugs that are derived from opium.drugs that are derived from opium.

What is the mechanism of the opioid What is the mechanism of the opioid receptors?receptors? These receptors hyperpolarize neurons These receptors hyperpolarize neurons

which causes analgesiawhich causes analgesia They open K channels to hyperpolarize the They open K channels to hyperpolarize the

cell, and some close Ca channelscell, and some close Ca channels They are G protein coupled receptorsThey are G protein coupled receptors

Describe the three receptor types.Describe the three receptor types. Mu receptorsMu receptors

99% of opioids act at this receptor99% of opioids act at this receptor Cause supraspinal analgesia, miosis, respiratory Cause supraspinal analgesia, miosis, respiratory

depression, euphoria, dependencedepression, euphoria, dependence DeltaDelta

Less well defined, also produces supraspinal and Less well defined, also produces supraspinal and spinal analgesia, possibly less dependencespinal analgesia, possibly less dependence

Sometimes agonists cause seizureSometimes agonists cause seizure

KappaKappa Spinal and some supraspinal analgesia. Weak Spinal and some supraspinal analgesia. Weak

miosis, sedation, some respiratory depression, miosis, sedation, some respiratory depression, dysphoriadysphoria

ReceptorologyReceptorology What receptors have the highest affinity for beta-What receptors have the highest affinity for beta-

endorphins?endorphins? These endogenous opioids have the highest affinity for mu and delta These endogenous opioids have the highest affinity for mu and delta

receptors.receptors. What receptor do enkephalins have the most affinity for?What receptor do enkephalins have the most affinity for?

Delta receptorsDelta receptors What about dynorphinsWhat about dynorphins

Kappa receptorsKappa receptors Are mu receptor agonists better for dull pain or sharp Are mu receptor agonists better for dull pain or sharp

pain?pain? Mu agonists are better for dull painMu agonists are better for dull pain

What are the three useful effects of exogenous opiate What are the three useful effects of exogenous opiate drugs?drugs? Activated mu receptors cause analgesia, both increasing the Activated mu receptors cause analgesia, both increasing the

threshold to pain and decreasing the response to pain (the latter threshold to pain and decreasing the response to pain (the latter being more important)being more important)

GI tract: increase tone and decrease motility due to mu receptor GI tract: increase tone and decrease motility due to mu receptor activationactivation

Great for anti-diarrheal but causes constipation in chronic pain patientsGreat for anti-diarrheal but causes constipation in chronic pain patients Antitussive Effects: suppression of cough Antitussive Effects: suppression of cough

What bad things happen acutely after one takes What bad things happen acutely after one takes opioids?opioids? Respiratory brain stem center depressionRespiratory brain stem center depression

Decreased response to carbon dioxide, decreased automaticityDecreased response to carbon dioxide, decreased automaticity Causes death in overdoseCauses death in overdose

MiosisMiosis Stimulation of edinger-westphal nucleus of 3Stimulation of edinger-westphal nucleus of 3rdrd cranial nerve. Little cranial nerve. Little

tolerance develops to pinpoint pupils.tolerance develops to pinpoint pupils. Sedation and EuphoriaSedation and Euphoria

Not mutually exclusive. Sedation may progress to sleep and coma, Not mutually exclusive. Sedation may progress to sleep and coma, while euphoria plays a role in reinforcement and addictionwhile euphoria plays a role in reinforcement and addiction

EmesisEmesis Direct stimulation of mu receptors in the chemoreceptor trigger Direct stimulation of mu receptors in the chemoreceptor trigger

zone. Also potentiate vestibular stimulation.zone. Also potentiate vestibular stimulation. CardiovascularCardiovascular

Release of histamine may result in mild hypotension.Release of histamine may result in mild hypotension. Urinary retentionUrinary retention

Inhibition of urinary voiding reflex (tolerance develops)Inhibition of urinary voiding reflex (tolerance develops) Biliary spasmBiliary spasm Chest wall rigidityChest wall rigidity

What receptor is responsible for most of the toxicities What receptor is responsible for most of the toxicities listed above?listed above? The Mu receptorThe Mu receptor

Tolerance and Tolerance and DependenceDependence

Define tolerance. Describe the clinical tolerance Define tolerance. Describe the clinical tolerance expected with opiate administration. Which 2 effects do expected with opiate administration. Which 2 effects do not develop tolerance?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 to opioids occurs to some effects but not others. More

tolerance occurs to depressant than stimulant effects, and can tolerance occurs to depressant than stimulant effects, and can cause 1000 fold dose-effect curve shiftage.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 Dependence is produced by repeated opiod exposure that manifests in a withdrawal syndrome when chronic exposure is manifests in a withdrawal syndrome when chronic exposure is abruptly discontinued.abruptly discontinued.

Both tolerance and dependence probaby result from upregulation Both tolerance and dependence probaby result from upregulation of the cAMP signal transduction pathway.of the cAMP signal transduction pathway.

What are the two types of dependence? Describe What are the two types of dependence? Describe withdrawal in regard to opioids.withdrawal in regard to opioids. Behavioral dependenceBehavioral dependence Physical dependencePhysical dependence

Withdrawal begins 6 hours after last dose, peaks at 48 hours, declines Withdrawal begins 6 hours after last dose, peaks at 48 hours, declines for 10 daysfor 10 days

Sweating, nausea, vomiting, ccramps, shivering, shakes, restlessness.Sweating, nausea, vomiting, ccramps, shivering, shakes, restlessness. Not life threatening, reversible in any stageNot life threatening, reversible in any stage

ChemistryChemistry What is the dependence mechanism?What is the dependence mechanism?

cAMP upregulation is a compensitory mechanism in chronic cAMP upregulation is a compensitory mechanism in chronic opioid administration.opioid administration.

What is the prototype mu agonist? How can you turn What is the prototype mu agonist? How can you turn morphine into heroin? Into Naloxone? How can you morphine into heroin? Into Naloxone? How can you increase potency? Increase kappa effects?increase potency? Increase kappa effects? MorphineMorphine Acetylation at 3- and 6 increases potency and creates heroinAcetylation at 3- and 6 increases potency and creates heroin Allyl substitutions at the N position (position 17) produces Allyl substitutions at the N position (position 17) produces

antagonists (naloxone)antagonists (naloxone) Stabilizing the C ring can greatly increase potencyStabilizing the C ring can greatly increase potency Loss of C ring increases kappa effectsLoss of C ring increases kappa effects

Which form of opioids are active?Which form of opioids are active? The Levo forms are activeThe Levo forms are active The dextro forms are much less active (hence The dextro forms are much less active (hence

dextromethorphan as OTC cough medicine)dextromethorphan as OTC cough medicine)

Describe the pharmacokinetics of morphine?Describe the pharmacokinetics of morphine? It has poor oral absorption and large first pass effect. 2-3 hour It has poor oral absorption and large first pass effect. 2-3 hour

half life. half life. Describe heroinDescribe heroin

Is 5-10 times more potent than morphineIs 5-10 times more potent than morphine It has greater lipid solubility than morphineIt has greater lipid solubility than morphine It has a very short (½ hour) half lifeIt has a very short (½ hour) half life

Shorter half life equals worse withdrawal symptomsShorter half life equals worse withdrawal symptoms Describe codeine.Describe codeine.

Orally effective (60% oral bioavailability)Orally effective (60% oral bioavailability) 2-4 hour half life2-4 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 It is less potent than morphine and has a shorter half life, and

has significant anticholinergic effects (dry mouth, mydriasis)has significant anticholinergic effects (dry mouth, mydriasis) Meperidine has an active metabolite (normeperidine) that is Meperidine has an active metabolite (normeperidine) that is

excitatory and works at non-opioid receptors.excitatory and works at non-opioid receptors.

How potent are fentanyl and congeners? How potent are fentanyl and congeners? What is their onset time?What is their onset time? These are very potent (100-1000x more potent These are very potent (100-1000x more potent

than morphine) and very short acting.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 Used for maintenance therapy for opioid addicts

due to oral activity and long duration of action.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 It is the only opioid with a dextro active form (ON TEST)TEST)

Is used orally and is less potent than morphineIs used orally and is less potent than morphine

A Mixed Agonist/Antagonist A Mixed Agonist/Antagonist and a Partial Agonistand a Partial Agonist

What is Pentazocine? For what and mixed What is Pentazocine? For what and mixed with what is it used?with what is it used? Partial agonist/antagonist at Mu receptors, as Partial agonist/antagonist at Mu receptors, as

well as analgesic activity at Kappa receptorswell as analgesic activity at Kappa receptors Often combined with naloxone for addictsOften combined with naloxone for addicts

What is buprenorphine used for? What is What is buprenorphine used for? What is its mechanism?its mechanism? Is sometimes used as a step down from Is sometimes used as a step down from

methadone therapy in addicts.methadone therapy in addicts. It is also an effective analgesic in non-addictsIt is also an effective analgesic in non-addicts

It is a partial agonist at mu receptors and It is a partial agonist at mu receptors and antagonist at kappa receptorsantagonist at kappa receptors

NaloxoneNaloxone

Why is naloxone a good drug for opioid Why is naloxone a good drug for opioid toxicity?toxicity? It is a pure mu antagonist with a very high It is a pure mu antagonist with a very high

affinity for mu receptors (displaces opioids). affinity for mu receptors (displaces opioids). Causes instant reversal of opioid overdose.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 Naltrexone is useful because it has a much

longer duration of action. Recently used for longer duration of action. Recently used for alcoholism.alcoholism.

What is unique about oxycodone?What is unique about oxycodone? It is a controlled release analgesic with much It is a controlled release analgesic with much

publicity on abuse potential.publicity on abuse potential.

Pain MedicinePain Medicine

Dr. Firnhaber—Feb 05, 2008Dr. Firnhaber—Feb 05, 2008

Pain!Pain! What is pain?What is pain?

An unpleasant sensory or emotional experience An unpleasant sensory or emotional experience associated with actual or potential tissue damage, or associated with actual or potential tissue damage, or described in terms of such damage. It is complex, described in terms of such damage. It is complex, multidimensional phenomenon that is sensory, multidimensional phenomenon that is sensory, perceptual, and subjective in nature.perceptual, and subjective in nature.

Pain is usually considered a symptom but is rarely Pain is usually considered a symptom but is rarely directly treateddirectly treated

What makes pain “chronic”? What are the two What makes pain “chronic”? What are the two categories of chronic pain?categories of chronic pain? Chronic pain lasts beyond the time that normal healing Chronic pain lasts beyond the time that normal healing

occurs (typically 3-6 months)occurs (typically 3-6 months) Maglignant chronic painMaglignant chronic pain Non-malignant chronic pain (benign pain, 1/3 of Non-malignant chronic pain (benign pain, 1/3 of

americans)americans) Includes headaches, low-back pain, arthritis, and othersIncludes headaches, low-back pain, arthritis, and others

Pain TypesPain Types What type of pain is the most difficult to treat?What type of pain is the most difficult to treat?

Non-malignant chronic painNon-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 opioidsNociceptive pain- responds well to opioids Somatic- intense and discrete, well localized, often aching or Somatic- intense and discrete, well localized, often aching or

throbbing. throbbing. Visceral- diffuse, episodic, and poorly localized. This pain Visceral- diffuse, episodic, and poorly localized. This pain

involves the internal organs and is propagated by sympathetic involves the internal organs and is propagated by sympathetic fibers.fibers.

NeuropathicNeuropathic Pain produced by the alteration of neurological structure and Pain produced by the alteration of neurological structure and

function. Different from nociceptive pain in that there is an function. Different from nociceptive pain in that there is an absence of continuous nociceptive input. Frequently has a absence of continuous nociceptive input. Frequently has a burning, lancinating, or electric shock quality, and persistent burning, lancinating, or electric shock quality, and persistent AllodyniaAllodynia. .

It does respond to opioids, but not as well as nociceptive painIt does respond to opioids, but not as well as nociceptive pain

Treatment ApproachesTreatment Approaches What are the “conservative” treatments of pain?What are the “conservative” treatments of pain?

NSAIDS or COX-2 inhibitors, muscle relaxants, NSAIDS or COX-2 inhibitors, muscle relaxants, membrane stabilizers, TCA/Anticonvulsantsmembrane stabilizers, TCA/Anticonvulsants

What are the other treatments of pain?What are the other treatments of pain? Physical therapy, interventional therapy, or opioidsPhysical 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 antagonistIt 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 While it has other functions, it is also a weak mu

receptor agonist.receptor agonist. How can you decrease pain in patients who are How can you decrease pain in patients who are

refractory to potent parenteral opioids?refractory to potent parenteral opioids? Either intrathecal opioids or nerve destructionEither intrathecal opioids or nerve destruction

Toxicity and AddictionToxicity and Addiction What organ toxicities are common with long term What organ toxicities are common with long term

opioid therapy?opioid therapy? None, actually safer in this respect than NSAIDsNone, actually safer in this respect than NSAIDs

May cause some impairment of immune function, but the clinical May cause some impairment of immune function, but the clinical importance of this is minimalimportance of this is minimal

What two effects do not get tolerance in long term What two effects do not get tolerance in long term opioid therapy?opioid therapy? miosis and decreased gastric motilitymiosis and decreased gastric motility

What is addiction?What is addiction? A behavioral pattern characterized by overwhelming A behavioral pattern characterized by overwhelming

involvement with the use of a drug, the securing of the involvement with the use of a drug, the securing of the supply, and the high tendancy to relapsesupply, 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 public19% in chronic pain patient, 16% of general public

DependenceDependence What is physcial dependence?What is physcial dependence?

The potential for an abstinence syndrome, or withdrawal following The potential for an abstinence syndrome, or withdrawal following abrupt dose reduction, discontinuation, or administration of an abrupt dose reduction, discontinuation, or administration of an antagonist.antagonist.

Is there a hypothesis that tolerance develops due to continuous Is there a hypothesis that tolerance develops due to continuous stimulation of the NMDA receptor?stimulation of the NMDA receptor? Yes, again this is why methodone does not develop tolerance very Yes, again this is why methodone does not develop tolerance very

oftenoften How does one manage tolerance?How does one manage tolerance?

Start with a differential diagnosis and ruling out any new problem Start with a differential diagnosis and ruling out any new problem that is causing painthat is causing pain

Next you can increase the dose or use an alternative opioid at a Next you can increase the dose or use an alternative opioid at a reduced dosereduced dose

Or you can use alternative pain management stratagies (drug Or you can use alternative pain management stratagies (drug holidays combined with other drugs)holidays combined with other drugs)

What is pseudoaddiction?What is pseudoaddiction? Refers to the perception by observers of drug-seeking behavior in Refers to the perception by observers of drug-seeking behavior in

patients who have severe pain and are undermedicated or who have patients who have severe pain and are undermedicated or who have not received other effective pain treatment interventionsnot received other effective pain treatment interventions

Looks like drug-seeking, but different in that when higher doses are Looks like drug-seeking, but different in that when higher doses are provided and pain is effectively treated, these behaviors disappearprovided and pain is effectively treated, these behaviors disappear

How is the maximum dose of opioids How is the maximum dose of opioids determined?determined? Keep going up until pain is effectively treated or Keep going up until pain is effectively treated or

side effects are limitingside 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 All opioids have a street value, 2.6 million americans report using analgesics for non-americans report using analgesics for non-medical reasonsmedical reasons

How might one treat “complex regional How might one treat “complex regional pain syndrome” of the upper extremity?pain syndrome” of the upper extremity? Stellate ganglion and lumbar sympathetic blockStellate ganglion and lumbar sympathetic block

Interventional crapInterventional crap What are the following indicated for?What are the following indicated for?

Celiac blockCeliac block Acute and chronic pancreatitis, pancreatic carcinoma, Acute and chronic pancreatitis, pancreatic carcinoma,

upper abdominal malignanciesupper abdominal malignancies Lumbar sympatheticLumbar sympathetic

Complex regional pain syndromes of the lower extremity, Complex regional pain syndromes of the lower extremity, vascular insufficiencyvascular insufficiency

Superior hypogastricSuperior hypogastric Mid-gut and colon malingnancies, sometimes rectal and Mid-gut and colon malingnancies, sometimes rectal and

pelvic malignanciespelvic malignancies For all of those other interventional therapies For all of those other interventional therapies

on page 102 of the syllabus, my suggestion is on page 102 of the syllabus, my suggestion is just guess based on where in the body is just guess based on where in the body is affected (e.g. affected (e.g. cervicalcervical epidural steroid epidural steroid injection for injection for cervicalcervical radiculopathy). If you radiculopathy). If you want to memorize it, have fun with that.want to memorize it, have fun with that.

Atypical deliveryAtypical delivery Why is neuraxial drug delivery sometimes preferable? When Why is neuraxial drug delivery sometimes preferable? When

is it indicated?is it indicated? It can be effective for multiple pains, is nondestructive, requires It can be effective for multiple pains, is nondestructive, requires

lower doses with lower side effectslower doses with lower side effects When maximal medical therapy has failed in the treatment of When maximal medical therapy has failed in the treatment of

chronic pain with known pathophysiology that is sensitive to the chronic pain with known pathophysiology that is sensitive to the infused agent. It helps if the patient/family have realistic infused agent. It helps if the patient/family have realistic expectationsexpectations

What is the most used local anesthetic for intrathecal pain What is the most used local anesthetic for intrathecal pain management?management? BupivacaineBupivacaine

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 What muscle relaxant is good for cerebral palsy? What is the new FDA approved drug for intrathecal pain?new FDA approved drug for intrathecal pain? BaclofenBaclofen ziconotideziconotide

There is way more information on pages 103-104, but I’m There is way more information on pages 103-104, but I’m probably not learning it.probably not learning it.

Nicotine and Nicotine and Other stimulantsOther stimulants

Dr. Owens, Feb 05, 2008Dr. Owens, Feb 05, 2008

Stimulants of abuseStimulants of abuse What are the two main forms of abused cocaine? Describe What are the two main forms of abused cocaine? Describe

each.each. Cocaine hydrochlorideCocaine hydrochloride

Can be sniffed as a “line” or “shot” ivCan 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 baseCocaine free base Crack or rock cocaine, which is volatilized for inhalation. Onset is even Crack or rock cocaine, which is volatilized for inhalation. Onset is even

fasterfaster Who developed free-basing?Who developed free-basing?

The tobacco industry developed it to serve their purposes. They were The tobacco industry developed it to serve their purposes. They were hanging out with Hitler and Genghis Kahn a lot at the time.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 These drugs kidnap people’s reward centers. Many addiction scientist

relate it to the experience of an orgasm.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 Initially, there is a very pleasurable “rush,” a feeling with sexual overtonesovertones

Euphoria, increased energy, increased sensory awareness, decreased Euphoria, increased energy, increased sensory awareness, decreased need for sleep, anorexia, increased activityneed for sleep, anorexia, increased activity

Post euphoria—Increased anxiety, suspicion of others, delusions, Post euphoria—Increased anxiety, suspicion of others, delusions, paranoia paranoia

Increased heart rate, blood pressure, incidence of strokeIncreased heart rate, blood pressure, incidence of stroke

KineticsKinetics 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 Used to treat the side effects of the excess stimulation caused by

cocaine.cocaine. What is the half life of cocaine?What is the half life of cocaine?

45 minutes45 minutes Most addicts like the initial rush and do not care for the next 40-80 Most addicts like the initial rush and do not care for the next 40-80

minutes of feeling.minutes of feeling. Describe the metabolism of cocaine. What metabolite is Describe the metabolism of cocaine. What metabolite is

created when cocaine is used with alcohol?created when cocaine is used with alcohol? It is cleared at about 3000mL/min due to extrahepatic It is cleared at about 3000mL/min due to extrahepatic

metabolism, this results in the very short half life. Urine metabolism, this results in the very short half life. Urine metabolites (benzoylecognine) are detectable for 3-4 days.metabolites (benzoylecognine) are detectable for 3-4 days.

Cocaethylene is created when cocaine and alcohol are Cocaethylene is created when cocaine and alcohol are coadministeredcoadministered

Tolerance and Tolerance and DependenceDependence

Describe cocaine tolerance.Describe cocaine tolerance. MinimalMinimal tolerance develops, and there is some evidence of tolerance develops, and there is some evidence of

sensitization to some effectsensitization to some effect Describe the physical dependence to cocaine.Describe the physical dependence to cocaine.

There is little or no physical dependence, though cocaine There is little or no physical dependence, though cocaine produces one of the most powerful behavioral and produces one of the most powerful behavioral and physiological dependence of any drug of abuse.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 Cocaine blocks the reuptake of released catecholamines and

5-hydroxytryptamine as well as dopamine reuptake5-hydroxytryptamine as well as dopamine reuptake Blocking Blocking dopamine reuptakedopamine reuptake seems to be responsible for CNS seems to be responsible for CNS

effects and abuse potentialeffects and abuse potential Describe the acutely cocaine overdosed patient.Describe the acutely cocaine overdosed patient.

The patient experiences paranoid aggression and The patient experiences paranoid aggression and cardiovascular crisis; he is dangerous.cardiovascular crisis; he is dangerous.

What are the new developments in the treatment and What are the new developments in the treatment and prevention of cocaine dependence?prevention of cocaine dependence? Cocaine antibodies to act as a pharmacokinetic antagonistCocaine antibodies to act as a pharmacokinetic antagonist

AmphetamineAmphetamine What isomer of amphetamine is most addictive?What isomer of amphetamine is most addictive?

d or (+) isomerd or (+) isomer Why is methamphetamine so dangerous Why is methamphetamine so dangerous

societally?societally? It is the second most abused drug in the world and It is the second most abused drug in the world and

produces large amounts of violence and criminalityproduces 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 In what ways does methamphetamine affect

neurotransmitter levels in the synapse?neurotransmitter levels in the synapse? It causes the release of catechol amines and 5-HT. It causes the release of catechol amines and 5-HT.

The CNS effects are thought to be mediated by The CNS effects are thought to be mediated by dopamine whereas the CV effects are produced by dopamine whereas the CV effects are produced by NE.NE.

CrystalCrystal Describe tolerance and dependence with Describe tolerance and dependence with

methamphetamine.methamphetamine. Tolerance is greater than with cocaine, strong behavioral Tolerance is greater than with cocaine, strong behavioral

dependence is mixed with physical dependence. dependence is mixed with physical dependence. In what ways is treatment of meth intoxication In what ways is treatment of meth intoxication

different from treatment of cocaine intoxication?different from treatment of cocaine intoxication? Treatment is more aggressive and more likely to require a Treatment is more aggressive and more likely to require a

benzo, alpha blocker, and/or an antipsychotic agent.benzo, alpha blocker, and/or an antipsychotic agent. What is kind of unique about methamphetamine What is kind of unique about methamphetamine

regarding serotonin?regarding serotonin? Meth users have depleted serotonin neurons, Meth users have depleted serotonin neurons,

neurotoxicity, and hyperstupidityneurotoxicity, and hyperstupidity Describe the typical meth head.Describe the typical meth head.

Patients often present as thin, hyperactive, paranoid, with Patients often present as thin, hyperactive, paranoid, with CV effects, bruxism (teeth grinding), and ultra-bad teethCV effects, bruxism (teeth grinding), and ultra-bad teeth

Smoking!!!! Hooray!!!!!Smoking!!!! Hooray!!!!! What percentage of deaths are related to smoking? What percentage of deaths are related to smoking?

Cancer cases?Cancer cases? 20% of deaths are related to smoking, 20% of new cancers are 20% of deaths are related to smoking, 20% of new cancers are

related to smoking.related to smoking. What percentage of smokers die from smoking?What percentage of smokers die from smoking?

1 of 2 smokers die from smoking1 of 2 smokers die from smoking Describe the withdrawal syndrome from nicotine.Describe the withdrawal syndrome from nicotine.

Anxiety, irritability, restlessness, difficulty concentrating, Anxiety, irritability, restlessness, difficulty concentrating, hunger, weight gain, insomnia, dysphoria hunger, weight gain, insomnia, dysphoria

Symptoms last 1-2 weeks, cravings can last much longer/indefinitelySymptoms last 1-2 weeks, cravings can last much longer/indefinitely What are the three main disease processes with What are the three main disease processes with

smoking?smoking? Cancer, heart disease, and chronic lung diseaseCancer, heart disease, and chronic lung disease

Of the many toxic chemicals in cigarette smoke, which Of the many toxic chemicals in cigarette smoke, which are the most potent carcinogens?are the most potent carcinogens? Aromatic amines, nitrosamines, and polyaromatic hydrocarbonsAromatic amines, nitrosamines, and polyaromatic hydrocarbons

Smoking PathogenesisSmoking Pathogenesis

What is the chief metabolic product of nicotine? What is the chief metabolic product of nicotine? What molecule is a good indication of recent What molecule is a good indication of recent smoking?smoking? CotinineCotinine CarboxyhemoglobinCarboxyhemoglobin

Does nicotine cause cancer?Does nicotine cause cancer? nono

What is the mechanism of smoking induced What is the mechanism of smoking induced cardiovascular disease?cardiovascular disease? Carbon monoxide decreases oxygen delivery to Carbon monoxide decreases oxygen delivery to

tissues. Nicotine activates sympathetic system tissues. Nicotine activates sympathetic system (release of catechol amines) and causes glucose (release of catechol amines) and causes glucose intolerance. Oxidant gases play a role.intolerance. Oxidant gases play a role.

COPD and Quitting COPD and Quitting

What is the mechanism of smoking-induced What is the mechanism of smoking-induced COPD?COPD? Irritant gases and cilotoxic agents produce Irritant gases and cilotoxic agents produce

structural abnormalities in cilia and impair structural abnormalities in cilia and impair clearance. Mucous glands become hyperplastic clearance. Mucous glands become hyperplastic causing increased mucous and cough. Excess causing increased mucous and cough. Excess elastase activity destroys alveolar septa (producing elastase activity destroys alveolar septa (producing emphysema).emphysema).

How effective is medication in helping people How effective is medication in helping people quit smoking?quit smoking? It is useful in motivated patients, particularly for It is useful in motivated patients, particularly for

the early withdrawal stage of quitting. Medication the early withdrawal stage of quitting. Medication aproximately doubles the quit rate achievable with aproximately doubles the quit rate achievable with counseling alone.counseling alone.

CNS Stimulants: CNS Stimulants: Theapuetic Uses Theapuetic Uses

and Toxicityand ToxicityFebruary 07, 2008February 07, 2008

Galen R. WengerGalen R. Wenger

Chemical ConvulsantsChemical Convulsants What are the chemical convulsants?What are the chemical convulsants?

Strychnine (common AR rodenticide), picrotoxin, and Strychnine (common AR rodenticide), picrotoxin, and pentylenetetrazolpentylenetetrazol

What is the mechanism of stychnine? Of picrotoxin What is the mechanism of stychnine? Of picrotoxin and pentylenetetrazol?and pentylenetetrazol? Blocks postsynaptic inhibition of glycine in the spinal Blocks postsynaptic inhibition of glycine in the spinal

cord.cord. Picro and penty block presynaptic inhibition produced Picro and penty block presynaptic inhibition produced

by GABA in all areas of the brain and probably bind to a by GABA in all areas of the brain and probably bind to a site within the pore of the GABAsite within the pore of the GABAAA receptor. receptor.

For what were chemical convulsants previously For what were chemical convulsants previously used?used? Stimulation of respiration in treatment of depressant Stimulation of respiration in treatment of depressant

overdose. This treatment was great at increasing death overdose. This treatment was great at increasing death rates, if you’re into that.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!)

Strychnine poisoningStrychnine poisoning What kind of seizure What kind of seizure

does strychnine does strychnine poisoning cause?poisoning cause? Opisthotonic seizure Opisthotonic seizure

(shown to the right)(shown to the right) How are these How are these

seizures and seizures and strychnine poisoning strychnine poisoning treated?treated? IV diazepam, dark IV diazepam, dark

quiet room, activated quiet room, activated charcoal if drug is still charcoal if drug is still in GI tract.in GI tract.

MethylxanthinesMethylxanthines What are the two methylxanthines (that we What are the two methylxanthines (that we

covered)?covered)? Caffeine and theophylline (both are present in tea, by Caffeine and theophylline (both are present in tea, by

the way)the way) What are the CNS effects of 85-250 mg of caffeine? What are the CNS effects of 85-250 mg of caffeine?

The cardiovascular system? The musculature?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 Decrease in rate at low dose, tachycardia and

increased CO at higher doseincreased CO at higher dose Constricts the vasculature of the CNSConstricts the vasculature of the CNS

Increased capacity for work with performance Increased capacity for work with performance enhancing effectsenhancing effects

How does caffeine increase urine output?How does caffeine increase urine output? The mechanism is unclear, increased CO with some The mechanism is unclear, increased CO with some

change in kidney function (urine composition similar change in kidney function (urine composition similar to thiazide diuretic use)to thiazide diuretic use)

Mechanism and KineticsMechanism and Kinetics What is the currently accepted mechanism of What is the currently accepted mechanism of

methylxanthines?methylxanthines? Antagonism of adenosine is probably responsible for Antagonism of adenosine is probably responsible for

most of these drugs’ effects.most of these drugs’ effects. Translocation of CaTranslocation of Ca++++, inhibition of phosphodiesterase , inhibition of phosphodiesterase

(with increased cAMP) also occur in vitro, but may not (with increased cAMP) also occur in vitro, but may not be important clinically.be important clinically.

What is the half life of methylxanthines? What What is the half life of methylxanthines? What percentage is metabolized before excretion?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 Half life is variable: long in liver diseased pregnant women on contraceptive pills, short in smokers taking phenytoin and contraceptive pills, short in smokers taking phenytoin and barbiturates (yes I know that pregnant women don’t usually barbiturates (yes I know that pregnant women don’t usually take contraceptive pills)take contraceptive pills)

>90%>90%

Toxicity and DependenceToxicity and Dependence What toxicities are noticed with high What toxicities are noticed with high

doses of methylxanthines?doses of methylxanthines? Nervousness, insomnia, delirium, Nervousness, insomnia, delirium,

convulsions (not usually fatal)convulsions (not usually fatal) Is caffeine mutagenic or teratogenic?Is caffeine mutagenic or teratogenic?

Maybe, it does cause little mutated plant Maybe, it does cause little mutated plant babies.babies. Copout answer—“advise pregnant women to use Copout answer—“advise pregnant women to use

caution and moderation”caution and moderation” Define physical dependence (again).Define physical dependence (again).

Upon abrupt discontinuation of a drug, Upon abrupt discontinuation of a drug, physical withdrawal symptoms occur. physical withdrawal symptoms occur.

AmphetaminesAmphetamines What are the amphetamine class psychomotor What are the amphetamine class psychomotor

stimulants (4)?stimulants (4)? Amphetamine, methamphetamine, methylphenidate, Amphetamine, methamphetamine, methylphenidate,

phenterminephentermine 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 & Methamphetamine > d-amphetamine > L-amphetamine &

methylphenidatemethylphenidate What are the primary CNS effects of amphetamines?What are the primary CNS effects of amphetamines?

Stimulate medullary respiratory center, increase motor Stimulate medullary respiratory center, increase motor activity, elevate mood, insomnia, decrease fatigueactivity, elevate mood, insomnia, decrease fatigue

Mechanism and UseMechanism and Use What is the mechanism of amphetamines?What is the mechanism of amphetamines?

Major mechanism is probably a release of NE Major mechanism is probably a release of NE (periphery), dopamine, and maybe serotonin from (periphery), dopamine, and maybe serotonin from nerve endings. There is also an inhibition of reuptake nerve endings. There is also an inhibition of reuptake of transmitter by nerve endings as well as a possible of transmitter by nerve endings as well as a possible small direct action on catecholamine receptors.small direct action on catecholamine receptors.

What is the now abandoned therapeutic use of What is the now abandoned therapeutic use of amphetamines?amphetamines? Weight control by effect on appetite (lasts about two Weight control by effect on appetite (lasts about two

weeks)weeks) Now considered unethicalNow considered unethical

What are the current uses of amphetamines?What are the current uses of amphetamines? Attention Deficit Hyperactivity DisorderAttention Deficit Hyperactivity Disorder

Hyperkinetic syndrome / ADHD, a paradoxical effectHyperkinetic syndrome / ADHD, a paradoxical effect Methylphenidate and d-amphetamine have similar efficacyMethylphenidate and d-amphetamine have similar efficacy

NarcolepsyNarcolepsy

Tolerance and ToxicityTolerance and Toxicity Describe the physical dependence and Describe the physical dependence and

withdrawal experienced with amphetamines.withdrawal experienced with amphetamines. The dependence is called “withdrawal of the The dependence is called “withdrawal of the

amphetamine type” and is basically the opposite of the amphetamine type” and is basically the opposite of the amphetamine effects (eat a lot, sleep a lot)amphetamine effects (eat a lot, sleep a lot)

What are the adverse effects of amphetamines in What are the adverse effects of amphetamines in children? What toxicities occur?children? What toxicities occur? In children, insomnia, abdominal pain, anorexia, weight In children, insomnia, abdominal pain, anorexia, weight

loss,loss, Following high doses of amphetamines, a psuedo-Following high doses of amphetamines, a psuedo-

psychotic syndrome develops:psychotic syndrome develops: Visual hallucinations predominante with some auditory Visual hallucinations predominante with some auditory

hallucinations, paranoid thoughts, changes in affect, hallucinations, paranoid thoughts, changes in affect, prounounced sympathetic effects.prounounced sympathetic effects.

The AlcoholsThe Alcohols

Feb 08, 2008Feb 08, 2008

Ethanol basicsEthanol 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. 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 Huge doses are administered, and it is the only drug in western society in which self-induced intoxication is legally acceptable and society in which self-induced intoxication is legally acceptable and socially ultra-cool.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/kgHumongenormous doses, around 1-3 grams/kg Minimal effect in man below 15 gramsMinimal 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 Passive diffusion in the stomach, small intestine, and colon. It will

occur up to a concentration of about 50%, at higher concentrations occur up to a concentration of about 50%, at higher concentrations (funneling everclear) it directly damages the GI system.(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 lungEthanol 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 Ethanol is distributed into total body water and is absorbed into

organs and tissues based on their blood supply.organs and tissues based on their blood supply.

KineticsKinetics How is expired air used to measure blood alcohol How is expired air used to measure blood alcohol

content?content? Ethanol in 2100mL of expired air is equal to ethanol present in Ethanol in 2100mL of expired air is equal to ethanol present in

1mL of blood at a wide range of concentrations1mL of blood at a wide range of concentrations How is mg% related to g/dLHow is mg% related to g/dL

100 mg% = 0.1 g/dL100 mg% = 0.1 g/dL What are the two routes of ethanol metabolismWhat 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 Conversion of ethanol to acetaldehyde by alcohol dehydrogenase (the first step) is rate limiting and typically saturated.(the first step) is rate limiting and typically saturated.

Both steps use NAD and result in NADH productionBoth 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 orderDue to saturation of alcohol dehydrogenase, 0 order 7-10 grams of ethanol per hour is metabolized7-10 grams of ethanol per hour is metabolized

What is the maximum amount of calories absorbed from What is the maximum amount of calories absorbed from alcohol per day?alcohol per day? 1100-1200 calories per day1100-1200 calories per day

Tolerance, Mechanism, Tolerance, Mechanism, MellanbyMellanby

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 What is the legal level of alcohol in blood in most states (including

arkansas)?arkansas)? 0.08 g/dL0.08 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 Not fully understood, there is an interaction with protein structures

affecting neuronal excitability. Many ion channels are also affected, affecting neuronal excitability. Many ion channels are also affected, including GABA, nicotinic, and glutamate receptors.including GABA, nicotinic, and glutamate receptors.

Replaces water in protein cavities which affects protein structureReplaces water in protein cavities which affects protein structure What is the maximum tolerance to alcohol observed? What is What is the maximum tolerance to alcohol observed? What is

responsible for the drug dispositional tolerance?responsible for the drug dispositional tolerance? About two fold, which is a minimal tolerance compared with other About two fold, which is a minimal tolerance compared with other

drugs (e.g. marijuana 1000x tolerance has been observed)drugs (e.g. marijuana 1000x tolerance has been observed) Induction of microsomal P450 system (as well as a pharmacodynamic Induction of microsomal P450 system (as well as a pharmacodynamic

tolerance)tolerance) Is alcohol cross-tolerant to other CNS depressants?Is alcohol cross-tolerant to other CNS depressants?

YesYes What is the Mellanby effect?What is the Mellanby effect?

People seem to be behaviorally drunk at about .08 g/dL on the 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 ascending (becoming drunk) end of the curve, but they sober up at higher levels on the down slope (after discontinuation)higher levels on the down slope (after discontinuation)

Withdrawal of ethanolWithdrawal of ethanol

Does physical dependence occur? Does physical dependence occur? Describe it.Describe it. Yes, it’s a two part withdrawal syndromeYes, it’s a two part withdrawal syndrome Peak effects occur at 24-48 hours, withdrawal Peak effects occur at 24-48 hours, withdrawal

lasts 5-7 days. Withdrawal occurs in two lasts 5-7 days. Withdrawal occurs in two phases:phases:

Phase 1-Phase 1- Hyperirritability, exaggerated reflexes, sleeplessness, Hyperirritability, exaggerated reflexes, sleeplessness,

tremor, muscular tension, cold sweaty skin, nausea, thirsttremor, muscular tension, cold sweaty skin, nausea, thirst Phase 2- (Delirium Tremens)Phase 2- (Delirium Tremens)

Severe hyperactivity with delirium, hallucinations, fever, Severe hyperactivity with delirium, hallucinations, fever, profuse sweating, intense vasodilation, severe profuse sweating, intense vasodilation, severe tachycardia, tonic-clonic seizurestachycardia, tonic-clonic seizures

Adverse EffectsAdverse 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 Either slowly reduce the ethanol dose, or switch to another CNS depressant and slowly lower that dose another CNS depressant and slowly lower that dose (usually benzos)(usually benzos)

What are the (adverse) effects of ethanol on the What are the (adverse) effects of ethanol on the liver? The GI tract? The endocrine system? The liver? The GI tract? The endocrine system? The kidney?kidney? Induction of P450, fatty degeneration of the liver, can Induction of P450, fatty degeneration of the liver, can

lead to cirrhosislead to cirrhosis Erosive gastritisErosive gastritis Gynecomastia, testicular atrophy, interference with Gynecomastia, testicular atrophy, interference with

release of prolactin, growth hormone, and antidiuretic release of prolactin, growth hormone, and antidiuretic hormonehormone

Decreased release of ADH with increased fluid intakeDecreased release of ADH with increased fluid intake

ToxicityToxicity Why don’t people usually drink enough ethanol to kill Why don’t people usually drink enough ethanol to kill

themselves?themselves? They usually lapse into a “coma” before they are able to They usually lapse into a “coma” before they are able to

drink enough ethanol to kill themselvesdrink enough ethanol to kill themselves What emergent condition can be misdiagnosed as ethanol What emergent condition can be misdiagnosed as ethanol

intoxication?intoxication? Diabetic comaDiabetic 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 hemodialysisEnhance elimination with gastric lavage or hemodialysis Supportive care: keep him breathing and perfusing Supportive care: keep him breathing and perfusing

tissues, correct metabolic acidosis, decrease intracranial tissues, correct metabolic acidosis, decrease intracranial pressure (mannitol), prevent aspiration of vomitus.pressure (mannitol), prevent aspiration of vomitus.

What percent of chronic alcoholics have liver damage? What percent of chronic alcoholics have liver damage? Cirrhosis?Cirrhosis? 100%100% 20%20%

Chronic AlcoholismChronic Alcoholism How do you treat wernicke korsakoff?How do you treat wernicke korsakoff?

High dose thiamineHigh dose thiamine How common is fetal alcohol syndrome? What are How common is fetal alcohol syndrome? What are

its three primary features for diagnosis? How its three primary features for diagnosis? How much maternal consumption of ethanol is needed much maternal consumption of ethanol is needed for “definite risk”?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 Microcephaly, prenatal growth deficiency, short

palpebral fissurespalpebral fissures Definite risk with intake above 3/oz per dayDefinite 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, SSRIsPharmacologic- disulfiram, naltrexone, SSRIs 12 step program12 step program

DisulfiramDisulfiram

Who is disulfiram good for? How does Who is disulfiram good for? How does it work?it work? Highly motivated patientsHighly motivated patients It inhibits aldehyde dehydrogenase, It inhibits aldehyde dehydrogenase,

increasing levels of acetaldehyde (aldehyde increasing levels of acetaldehyde (aldehyde syndrome created)syndrome created) Feels like a myocardial infarctionFeels 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, It is used as a solvent for many other drugs,

to cool the skin (alcohol baths), as a to cool the skin (alcohol baths), as a sedative, and as a “head-cold” remedysedative, and as a “head-cold” remedy

Wood Alcohol Wood Alcohol What are the initial symptoms of methanol? What What are the initial symptoms of methanol? What

are the toxic symptoms? What is the cause of death are the toxic symptoms? What is the cause of death in overdose?in overdose? A mild drunk: euphoria, muscle weakness, disinhibitinA mild drunk: euphoria, muscle weakness, disinhibitin Within 3-36 hours, a series of toxic symptoms including: Within 3-36 hours, a series of toxic symptoms including:

N/V, headache, delirium, GI pain, back pain, cold clammy N/V, headache, delirium, GI pain, back pain, cold clammy hands, hyperemic optic disks.hands, hyperemic optic disks.

Severe cases include a metabolic acidosis with an anion gap, fixed Severe cases include a metabolic acidosis with an anion gap, fixed dilated pupils, retinal damage, bradycardia, coma, seizuresdilated pupils, retinal damage, bradycardia, coma, seizures

Immediate cause of death is respiratory arrestImmediate 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 The metabolism of methanol is to formaldehyde and formic acid. These metabolites produce toxicity and formic acid. These metabolites produce toxicity and acidosisacidosis

How do you treat methanol poisoning?How do you treat methanol poisoning? Maintain airway, infusion sodium bicarbonate, administer Maintain airway, infusion sodium bicarbonate, administer

large doses of ethanol (use up the aldehyde large doses of ethanol (use up the aldehyde dehydrogenase)dehydrogenase)

Can use hemodialysis, emesis.Can use hemodialysis, emesis.

Cannabinoids Cannabinoids and and

HallucinogensHallucinogensW.D. Wessinger W.D. Wessinger

February 11, 2008February 11, 2008

MarijuanaMarijuana What is marijuana? What is Hashish?What is marijuana? What is Hashish?

Dried parts of the cannabis plant, usually leaves and Dried parts of the cannabis plant, usually leaves and flower heads that are used as a smoking mixtureflower heads that are used as a smoking mixture

Dried resinous exudates of the flowering topsDried resinous exudates of the flowering tops What is the most abundant psychoactive agent in What is the most abundant psychoactive agent in

marijuana? marijuana? Delta-9-tetrahydrocannabinal, which makes up 0.5-Delta-9-tetrahydrocannabinal, which makes up 0.5-

11% of the weight of marijuana.11% of the weight of marijuana. Describe the effects of marijuana.Describe the effects of marijuana.

Euphoria, altered perceptions, impaired short term Euphoria, altered perceptions, impaired short term memory, impaired balance, decreased memory, impaired balance, decreased concentration/attention, 4-8 hour impairment post-concentration/attention, 4-8 hour impairment post-euphoria.euphoria.

Pharmacology of Pharmacology of MarijuanaMarijuana

What effects does marijuana have on the cardiovascular What effects does marijuana have on the cardiovascular system?system? Increases of 20-50 bpm, pulse of 140 bpm can occur.Increases of 20-50 bpm, pulse of 140 bpm can occur. Increased blood pressure while lying down but decreased while Increased blood pressure while lying down but decreased while

standing.standing. Vasodilation of scleral and conjunctival vessels resuting in blood shot Vasodilation of scleral and conjunctival vessels resuting in blood shot

eyes.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, Frank hallucinations, anxiety and panic replace euphoria, delusions, paranoid feelingsparanoid feelings

Describe cannabinoid CB1 receptors. CB2 receptors.Describe cannabinoid CB1 receptors. CB2 receptors. These G-protein coupled receptors are widely distributed throughout These G-protein coupled receptors are widely distributed throughout

the CNS, especially in the cortex, hippocampus, mesolimbic area, the CNS, especially in the cortex, hippocampus, mesolimbic area, cerebellum, medulla, and substantia nigra.cerebellum, medulla, and substantia nigra.

CB2 receptors are found in the periphery, mostly associated with CB2 receptors are found in the periphery, mostly associated with immune tissuesimmune tissues

What is the endogenous ligand for these receptors?What is the endogenous ligand for these receptors? Anandamide, an arachidonic acid derivativeAnandamide, an arachidonic acid derivative

Tolerance and LegalityTolerance and Legality What are the long term problems with marijuana What are the long term problems with marijuana

use?use? Memory and learning problems, anxiety and panic Memory and learning problems, anxiety and panic

attacks, loss of judgment, drug testing, and jail.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 Marijuana is classified as a chedule I drug (with no recognized medical value and a high abuse potential), but recognized medical value and a high abuse potential), but synthetic THC is a schedule II drug that is FDA approved synthetic THC is a schedule II drug that is FDA approved for a few indications. They are:for a few indications. They are:

Anti emetic for cancer chemotherapyAnti emetic for cancer chemotherapy Appetite stimulant in AIDS wasting syndromeAppetite stimulant in AIDS wasting syndrome

Other proposed uses include anticonvulsant, muscle spasm and Other proposed uses include anticonvulsant, muscle spasm and decreasing intraocular pressure.decreasing intraocular pressure.

Lysergic acid Lysergic acid diethylamidediethylamide

Describe LSD (chemically).Describe LSD (chemically). Lysergic acid diethylamide is an ergot alkaloid derived semi-synthetically Lysergic acid diethylamide is an ergot alkaloid derived semi-synthetically

from the fungus Claviceps purpurea that grows on grains such as wheat and from the fungus Claviceps purpurea that grows on grains such as wheat and rye.rye.

Chemically it is an indolealkylamine that is structurally similar to NE, Chemically it is an indolealkylamine that is structurally similar to NE, dopamine and serotonin.dopamine and serotonin.

How much LSD is required to produce an effect?How much LSD is required to produce an effect? 20-25 20-25 micromicrograms can produce an effect.grams 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 Visual hallucinations that are elaborated from visual disturbances such as

prolonged afterimages and an overlapping of present and past perceptions.prolonged afterimages and an overlapping of present and past perceptions. Auditory hallucinations are rareAuditory hallucinations are rare

What are the other effects of LSD?What are the other effects of LSD? Increased blood pressure, dilated pupils, piloerection, hyperreflexia, pyrexiaIncreased blood pressure, dilated pupils, piloerection, hyperreflexia, pyrexia

What is the mechanism of LSD?What is the mechanism of LSD? Probably an agonist at 5-HTProbably an agonist at 5-HT22, though it probably also affects many other , though it probably also affects many other

receptorsreceptors Give the five dollar word for flashbacks? Give the five dollar word for flashbacks?

Hallucinogen persisting perception disorderHallucinogen persisting perception disorder Can LSD precipitate serious depression or prolonged shizophrenic Can LSD precipitate serious depression or prolonged shizophrenic

episodes?episodes? yesyes

LSD LSD

Does tolerance occur with LSD?Does tolerance occur with LSD? Yes, it appears rapidly and goes away Yes, it appears rapidly and goes away

rapidly.rapidly. Cross-tolerance to other hallucinogens like Cross-tolerance to other hallucinogens like

beta phenylethylamines and psilocybin.beta phenylethylamines and psilocybin. Does dependence occur with LSD?Does dependence occur with LSD?

NoNo What is LSD used for medically?What is LSD used for medically?

LSD is a schedule I drug with no recognized LSD is a schedule I drug with no recognized medical uses.medical uses.

Peyote and XPeyote and X What is MDMA?What is MDMA?

MethyleneDioxyMethAmphetamine, or ecstacy, is a MethyleneDioxyMethAmphetamine, or ecstacy, is a beta phenylethylamine hallucinogen. It is the newest beta phenylethylamine hallucinogen. It is the newest in this class and is the successor to MDA.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 3,4-methylenedioxyamphetamine is also known as

mescaline and is the active component of the peyote mescaline and is the active component of the peyote cactus.cactus.

It is a mild intoxicant producing euphoria without It is a mild intoxicant producing euphoria without frank hallucinationsfrank 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 Psychotherapists used MDMA in the 70s to help

patients talk about their feelings. Then they played patients talk about their feelings. Then they played techno music put glow-sticks in their mouths.techno music put glow-sticks in their mouths.

MDMA toxicityMDMA toxicity What is it called when MDMA users take additional doses What is it called when MDMA users take additional doses

every couple of hours?every couple of hours? StackingStacking

What effects does MDMA have?What effects does MDMA have? Mild hallucinogen and stimulant, euphoria, clarity of emotions and Mild hallucinogen and stimulant, euphoria, clarity of emotions and

feeling of well being, hypersensitivity to touch, bruxism, increased feeling of well being, hypersensitivity to touch, bruxism, increased body temperaturebody temperature

What are the symptoms of MDMA toxicity?What are the symptoms of MDMA toxicity? Increased pulse and BP, heat exhaustion, brain Increased pulse and BP, heat exhaustion, brain

damage/neurotoxicity (decreased serotenergic functioning)damage/neurotoxicity (decreased serotenergic functioning) How much ecstacy is required to produce serotenergic How much ecstacy is required to produce serotenergic

damage?damage? One dose is plenty to decrease serotenergic function. Cognitive One dose is plenty to decrease serotenergic function. Cognitive

deficits occur.deficits occur. Is it a good idea to use phenothiazines for Is it a good idea to use phenothiazines for

phenylethylamine overdose? What is a better choice?phenylethylamine overdose? What is a better choice? Probably not because some people have died, probably due to the Probably not because some people have died, probably due to the

anticholinergic interaction with the sympathomimetic effect.anticholinergic interaction with the sympathomimetic effect. Benzodiazepines seem to be effective and are less dangerousBenzodiazepines seem to be effective and are less dangerous

Dissociative AnestheticsDissociative Anesthetics What is the prototype dissociative anesthetic? What is the prototype dissociative anesthetic?

What are the other dissociative anesthetics?What are the other dissociative anesthetics? Phencyclidine (PCP). I love its other names: angel dust, Phencyclidine (PCP). I love its other names: angel dust,

KW, rocket fuel, embalming fluid.KW, rocket fuel, embalming fluid. Phencyclidine, ketamine, and (I guess) Phencyclidine, ketamine, and (I guess)

dextromethorphan.dextromethorphan. Was phencyclidine ever used as a general animal Was phencyclidine ever used as a general animal

anesthetic? What is phencyclidine’s schedule?anesthetic? What is phencyclidine’s schedule? NoNo Schedule II, though analogs and precursors are Schedule II, though analogs and precursors are

schedule I.schedule I. What is Sherm’s?What is Sherm’s?

A street drug consisting of marijuana cigarettes A street drug consisting of marijuana cigarettes impregnanted with phencyclidine (“dipped in impregnanted with phencyclidine (“dipped in embalming fluid”)embalming fluid”)

Special K and Cough Special K and Cough SyrupSyrup

What is ketamine used for medically? What What is ketamine used for medically? What schedule is ketamine?schedule is ketamine? Pediatrics, burn patients, and in veterinary medicinePediatrics, burn patients, and in veterinary medicine Schedule IISchedule II

What schedule is dextromethorphan? Where is it What schedule is dextromethorphan? Where is it found?found? It is not a schedule drug and is available OTC in cold It is not a schedule drug and is available OTC in cold

and cough preps as an anti-tussive.and cough preps as an anti-tussive. What is the mechanism of the dissociative What is the mechanism of the dissociative

anesthetics?anesthetics? They all work by non-competitively antagonizing NMDA They all work by non-competitively antagonizing NMDA

receptors, binding to the NMDA receptor complex in the receptors, binding to the NMDA receptor complex in the ion channel, blocking it.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 Phencyclidine is the most potent and long lasting (6-10

hours)hours)

Effects, Dependence, Effects, Dependence, OverdoseOverdose

What are the effects of dissociative anesthetics?What are the effects of dissociative anesthetics? Euphoria/dysphoria, analgesia (reported as superhuman strength), Euphoria/dysphoria, analgesia (reported as superhuman strength),

motor incoordination, drunken ataxia, slurred speech, vertical motor incoordination, drunken ataxia, slurred speech, vertical nystagmusnystagmus

Hallucinations of both visual and auditory types: distortions of Hallucinations of both visual and auditory types: distortions of space, time, and body image, detachment from environment, space, time, and body image, detachment from environment, dissociation (“out-of-body”)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 Yes, both have been noted in animals, including withdrawal

syndromes.syndromes. What psychiatric (mis)diagnosis is often given to abusers of What psychiatric (mis)diagnosis is often given to abusers of

PCP?PCP? SchizophreniaSchizophrenia

What are the symptoms of PCP overdose?What are the symptoms of PCP overdose? Agitation alternating with stuporAgitation alternating with stupor Increased BP, psychosis, myoclonus, seizures, trauma?, Increased BP, psychosis, myoclonus, seizures, trauma?,

rhabdomyolysisrhabdomyolysismyoglobinuriamyoglobinuriarenal failurerenal failure Motor seizures and respiratory depression.Motor seizures and respiratory depression.

OverdoseOverdose

How might one treat PCP overdose?How might one treat PCP overdose? Just give diazepam and wait, everything Just give diazepam and wait, everything

else (antipsychotics, urinary else (antipsychotics, urinary acidification, talking them down) is bad.acidification, talking them down) is bad. And keep them from hurting themselves or And keep them from hurting themselves or

others.others.

Brain OverBrain Over

Good LuckGood Luck