Antipsychotic Agents: 1 st Generation

1. Antipsychotic Agents: 1st Generation

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

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

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

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

6. Adverse Effects—Motor • What motor adverse effect is common with the 1st generation antipsychotics in the first 5 days? Describe the syndrome. How is it treated? • Acute dystonia • Spasms of face, neck, and back • Treated with anticholinergics • What motor adverse effect is common with the 1st generation antipsychotics between days 5 and 60? Describe the syndrome. How is it treated? • Akathisia • is a syndrome characterized by unpleasant sensations of "inner" restlessness that manifests itself with an inability to sit still or remain motionless, hence its origin ancient Greek α (a), without, not +(káthisis), sitting] –http://en.wikipedia.org/wiki/Akathisia • Treat by lowering the dose and/or administering anticholinergics • What motor adverse effect is common with the 1st generation antipsychotics between days 5 and 30? Describe the syndrome. How is it treated? • (drug induced) parkinsonism • Looks like parkinson’s disease • Treat by lowering the dose and/or administering anticholinergics

7. Even more side effects • Describe the perioral tremor and its treatment. • The “rabbit syndrome” involves tremors around the nose and mouth and can occur months or years after beginning treatment with antipsychotics. It is treated like the others, with lowering the dose and/or anticholinergics • The secretion of which hormone is increased by 1st generation antipsychotics? Which two hormones are decreased? • Hyperprolactinemia occurs with these drugs • Decreased gonadotropin and estrogen release

8. Way more side effects • Do first generation antipsychotics cause edema or weight gain? • Yes, both • Which anti-psychotics (potency) cause more sedation? • The lower potency anti-psychotics cause more sedation • Which 1st generation antipsychotic is best to use in a patient with a history of seizures? • In general, these drugs lower seizure threshold and should be used carefully in patients with a history of seizures. Fluphenazine is the best choice in these patients. • What is neuroleptic malignant syndrome? What is its mortality? How is it treated? • A rare but life threatening condition which resembles a very severe form of parkinsonism with catatonia, autonomic instability (BP, pulse, temp), stupor and possibly myoglobinemia. • Mortality is >10% • Treatment includes discontinuing the antipsychotic and adminstering dantrolene, along with supportive care

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

10. Atypical Antipsychotics and Lithium January 29, 2008 “I’m so happy ‘cause today I found my friends, they’re in my head. I’m so ugly, that’s ok ‘cause so are you.”

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

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

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

14. Side effects for days • What are the most common side effects of risperidone? What are the initial side effects (elderly)? • Asthenia, insomnia, difficulty concentrating • Orthostatic hypotension and reflex tachycardia • Of the atypical antipsychotics, which has the highest incidence of extrapyramidal effects? Which causes the most hyperprolactinemia? • Risperidone • Risperidone • What are the main side effects of olanzapine? • Postural hypotension, somnolence, constipation, weight gain, diabetes, dizziness, sexual dysfunction, and akathisia (these are pretty much the normal atypical antipsychotic side effects) • Which two atypical antipsychotics cause the most weight gain? • Clozapine and olanzapine • What are the strange and different adverse effects of quetiapine? • Increased serum aminotransferase, cataracts (in dogs) • Which atypical antipsychotic causes the greatest elongation of the QT interval? What does this drug cause the least of? • Ziprasidone (so don’t use it with other QT prolonging drugs or arrhythmia pts.) • Of the atypical antipsychotics, ziprasidone causes the least weight gain.

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

16. More aripiprazole and conclusions • What are the side effects of aripiprazole? • Anxiety, headache, nauseas and vomiting, constipation, insomnia and somnolence, lightheadedness • No extrapyramidal effects, hyperprolactinemia, hyperlipidemia, hyperglycemia, or weight gain • Name three CYP 2D6 inhibitors. What should be done with aripiprazole if coadministered with any of these drugs? • Fluoxetine, paroxetine, quinidine • The dose of aripiprazole should be reduced if coadministered with any of the above • Why isn’t aripiprazole the only antipsychotic used by now? • While it is effective in treating schizophrenia without causing extrapyramidal symptoms, weight gain, hyperprolactinemia, or hyperlipidemia, aripiprazole has not been on the market long enough to evaluate its long term safety. • What are the differences between 1st and 2nd Generation antipsychotics? • They are roughly equally effective in treating psychosis • First generations have a higher incidence of extrapyramidal effects, while second generation have a higher incidence of weight gain, hyperglycemia, and hyperlipidemia • Second generation drugs are about 10x as expensive

17. Lithium Carbonate • How long does it take for lithium carbonate to work? What percentage of patients get their mood stabilized? • 2-3 weeks • Normalizes the mood of 80% of patients • What do you do if a patient is suffering from “an acute manic attack” currently? • Use an antipsychotic first, then introduce lithium later as the patient becomes stabilized • The low therapeutic index and severe toxicity of lithium require a cooperative and stable patient • Can lithium be used in patients with recurrent depression without mania? • According to this lecture yes, but it is much more dangerous than the SSRIs. • What is the current best guess as to the mechanism of lithium? • Downregulation of second messangers IP3 and DAG is currently considered the best possibility. • Other hypotheses include effects on ion transport or on serotonin and dopamine systems. • What is the half life of lithium? • About 20 hours • What is the therapeutic window of lithium? • 0.9 to 1.4 mEq/L

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

19. Other Drugs • What are two alternative drugs for bipolar disorder? • Carbamazepine and valproic acid • Why isn’t carbamazepine a great choice? • A controlled study in the VA system has shown it to be ineffective. • Why might you use valproic acid (Depakote) instead of lithium? • It appears to be as effective as lithium in the early weeks of treatment, it has fewer side effects, and the dose can be titrated up more quickly. • Long term efficacy has not been determined.

20. Dementia • How many americans are affected by dementia? • 4.5 million americans • 100 billion dollars annually • What is dementia? • An acquired persistent and progressive impairment in intellectual function, with compromise in at least one other cognitive domain (below) that impairs daily living. • Language, visuospatial, calculation, judgment, problem solving • What are the three most common forms of dementia in order of most to least? • Alzheimer’s (60-80%), vascular dementia, lewy body dementia • What neurotransmitter deficiency is theorized to be critical in the genesis of alzheimer’s disease? Where is one place in the brain that is particularly affected (loss of neurons)? • Acetylcholine • Nucleus basalis of meynert, which is the major source of Ach to the cortex. • Name the cholinesterase inhibitors. • Tacrine, donepezil, rivastigmine, galantamine • Name the NMDA receptor antagonist. • Memantine • Name all the other drugs that are FDA approved for the treatment of Alzheimer’s disease. • There are none

21. Alzheimer’s Disease • What is the first clinical feature of Alzheimer’s? • Impairment of short-term memory • Is a deficiency of acetylcholine critical in the genesis of the symptoms of alzheimer’s disease? • According to the cholinergic hypothesis, yes. • How does Tacrine funciton? • Centrally acting, noncompetitive, reversible cholinesterase inhibitor • Also blocks reuptake of dopamine, NE, and serotonin. Inhibits MAO • Blocks sodium and potassium channels • Partial muscarinic agonist • What is Tacrine’s half life? • 2-3.5 hours • What is the most important adverse effect of Tacrine? What adverse effects are common? • 50% of patients get hepatic toxicity • SLUD- salivation, lacrimation, urination, defecation • Nausea, vomiting, diarrhea, headache, myalgia, ataxia

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

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

24. Memantine • What patient population (severity of disease) are helped by Memantine? • Moderate to severe Alzheimer’s disease patients are helped by memantine. • Describe the mechanism of memantine. Why does this help? • Noncompetitive NMDA receptor antagonist. It is thought to prevent NMDA calcium channel opening at high firing rates (but not at lower, normal rates) • Excess NMDA activity is thought to be toxic to neurons, and to play a role in dying neurons reaching out and hurting their neighbor neurons • What clinical benefit does memantine cause? What is its half life and elimination mode? • Some reduced rate of cognitive deterioration (maybe) • 60-80 hours, excreted in urine. • Describe memantine’s side effects? • Dizziness, headache, constipation, hallucinations, confusion

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

26. Pharmacologic Management of Parkinsonism and Huntington’s

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

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

29. Medications • What were the first drugs used against parkinsonism? • Anticholinergics • For whom are these medicines still used? • Anticholinergics are used for psychotic patients (who shouldn’t take L-dopa) and for drug induced parkinsonism. They are also used in combination with L-dopa in some patients. • How long is the half life of L-dopa? • 3 hours, metabolized to dopamine (peripherally) • What is the high end of the dosing spectrum with L-dopa? • At least 8-10 grams per day can be used. • How do you prevent or limit side effects? • By titrating the dose up very slowly • What side effects are common with long term use of L-dopa? • Choreiform movements, mental confusion, delirium • N & V, orthostatic hypotension, arrhythmias also occur • N & V or N/V is nausea and vomiting • What drug interactions with L-dopa are problematic? Which one is useful? • MAOinhibitors (hypertensive crisis) and antipsychotics (antagonism) are contraindicated, pyridoxine (B6) causes rapid metabolism of L-dopa. • Carbidopa coadministration increases the percentage of L-dopa that crosses the BBB, reducing the necessary dose of L-dopa 7-10 fold.

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

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

32. Yo-yo-yoing holidays • What are the names of the (reversible) COMT inhibitors used? • Tolcapone and Entacapone • What are these drugs used for? • They are used as adjuvant therapy to increase the “on time” of the L-dopa (in patients with “wearing off”) • What is this wearing off business? How is it treated? • Some patients who take drugs every 6 hours get return of symptoms at 4-5 hours, thought to be caused by decreased central conversion to dopamine and decreased dopamine storage. • Also known as “end of dose deterioration” • Obviously, the easy way (for the doc) is to just make the patient take the medicine every three hours (at half the dose). • What is Peak dose dyskinesia? How is it treated? • Abnormal, involuntary movements which occur 1-2 hours after dosing. May involve excess dopamine) • Smaller and more frequent doses • What is yo-yo-ing? • Patients cycle back and forth in 30min intervals of doing well and doing poorly. This effect is not understood and is not related to dosing frequency or size. • Thought to be caused during a point where disease process is almost too severe to be relieved by drugs anymore. • How useful are drug holidays? • Not shown to be helpful

33. Huntington’s Chorea • How many people get Huntington’s? At what age? • 1/50,000 • Age 37-47 years • What are the early symptoms of Huntingtons? • catatonia, aggressive outbursts, psychotic behavior, exaggerated reflexes, good muscle strength, but weak tone • What are the later symptoms? • Progressively worsening dementia, increased appetite without weight gain • What are the final stage symptoms? • Greatly increased diet with weight loss, rigid motor tone, death within 10-15 years of onset of symptoms • What drugs improve the motor symptoms of Huntington’s? • Reserpine, phenothiazine and butyrophenone antipsychotics • What drugs make the motor symptoms worse? • L-dopa, anticholinergics, and dopamine agonists

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

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

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

37. Side effects • What are NSAIDs used for? • Pain, primary dysmenorrhea, joint inflammation (side effects are a problem when used for inflammation in rheumatism), fever, sunburn • What is the first line drug of choice for rheumatoid arthritis? • Aspirin in high doses • What are the most common side effects of the NSAIDs? What causes these problems? • GI distress, damge, bleeding/ulceration • Prostaglandins PGE2 and PGI2 decrease acid secretion and increase mucous production. NSAIDS decrease the formation of these prostaglandins and increase the likelihood of GI problems. Chronic use results in erosion of the stomach lining • What mediates NSAID renal effects? • PGI2 and PGE2 cause vasodilation of the afferent arteriole, which promotes GFR. NSAIDs decrease production of these chemicals and decrease GFR. • What mediates NSAID effects on platelet function and bleeding? • TXA2 makes platelets “sticky,” and is a potent vasoconstrictor (procoagulant). Epithelial cells produce PGI2 in response to platelet activity, which inhibits platelet aggregation. NSAIDs inhibit platelet TXA2 and PGI2 production, which can cause a net increased bleeding time.

38. Salicylate • What is the prototype Salicylate? How does it work? • Aspirin • It is an irreversible inhibitor of prostaglandin synthesis (binds COX nonselectively and irreversibly) • What is special about aspirin’s nonreversible mechanism? • Since aspirin binds COX irreversibly, it permanently reduces a platelet’s ability to aggregate. It’s effects on epithelial cells are minimal, however, as epithelial cells can make new COX. • What is aspirin metabolized to? How long is aspirin’s half life? What kinetics does aspirin follow? • Salicylic acid (the active agent) • 15 minutes (salicylic acid has a half life of 3-4 hours) • First order at low doses and zero order at high doses • How does pH affect the distribution of aspirin? • Decreased pH increases unionized drug available for distribution. Aspirin makes the blood more acidic.

39. Aspirin toxicities • What aspirin toxicity is common at higher therapeutic doses (2-4 g)? mild toxicity at 6-8g? Moderate toxcity at 8-10 g? Severe intoxication at 20-50 g? • Bleeding, decreased uric acid excretion, hypersensitivity reactions • Salicylism, tinnitus (early warning sign), increased metabolic rate (uncoupled mitochondria) with consequent fever, hyperventilation and respiratory alkalosis • Moderate toxicity causes respiratory depression with respiratory, chemical, and metabolic acidosis (which is exacerbated by the previous alkalosis). • Severe toxicity involves wild pH, hyperthermia, dehydration, loss of electrolytes, and is life threatening (coma, renal and respiratory failure). • How does one treat salicylate intoxication? • Cool, rehydrate, correct acid base and electrolyte imbalance • Prevent further absorption (emesis/lavage) • Alkalinize the urine to increase excretion • Hemodialysis • Diazepam for convulsions

40. NSAID varieties • For whom is aspirin contraindicated? • Patients with: renal disease, bleeding disorders, hypersensitivity, gout, and young children during or following a viral infection • Is ibuprofen another NSAID? How effective of an analgesic is it? Of an anti-inflammatory? What are ibuprofen’s side effects? • Yes • At low dose, it is more effective than aspirin at analgesia • At high doses, its anti-inflammatory action is just as good as aspirin • GI irritation and bleeding, rash, tinnitus w/dizziness, agranulocytosis, aplastic anemia, renal failure, interstitial nephritis, nephrotic syndrome. • What’s good about Naproxen? What’s bad about Naproxen? • Long half life (13 hours) • Intermediate potency (<ibuprofen or aspirin) • Has increased incidence of side effects (GI pain most common) compared to ibuprofen, likely due to need for increased dose • What is the most potent NSAID? What is it used for? What are its major toxicities? Half life? • Indomethacin • Used for acute gout, spondylitis, osteoarthritis, and is the drug of choice to close a patent ductus arteriosis • High incidence of GI distress and other toxicities (25% of patients will discontinue) • 4-5 hours

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

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

43. Management of Acetominophen overdose Dr. Laura James

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

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

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

47. Describe the four phases of acetominophen toxicity. • 0.5-24 hours • Nausea, vomiting, elevation of hepatic transaminases, or asymptomatic • 24-72 hours • Abdominal tenderness in RUQ. Elevated hepatic enzymes. Clotting factors impaired. May have renal involvement. • 72-96 hours • Sequelae of hepatic injury: jaundice, coagulation defects, hepatic encephalopathy, renal failure, death will happen in this phase • Hard to get history at this point. If you show up to the hospital now, it is hard to treat you. • 4-14 days • They get better and the liver fully recovers

48. Treatment • What kind of liver damage is done by acetominophen toxicity (a path. term)? • Centrilobular necrosis • Describe the treatment of acetominophen poisoning. Why is it important to treat quickly? What is the major adverse effect of this drug? • N-acetylcysteine (NAC) • Works at the glutathione step as a glutathione substitute to prevent “adduct” formation • IV NAC got approved in 2004 • Efficacy is highly dependent on the time of NAC relative to the overdose. • Treatment within 10 hours –6% risk of toxicity • 10-24 hours after overdose—26.4% risk of toxicity • Vomiting is the major side effect. Anaphylaxis is also a possibility, especially with IV dosing. • What treatments can be effective if administered within two hours of the overdose? • Activated charcoal • Do you treat the patients nausea and vomiting? • yes

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

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