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Page 1: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

Gastrointestinal System Gastrointestinal System DrugsDrugs

Page 2: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

Intro to fungal infectionIntro to fungal infection

What are fungi?What are fungi?– Eukaryotes lacking flagella that develop from sporesEukaryotes lacking flagella that develop from spores

In which patients do most fungal infections occur?In which patients do most fungal infections occur?– The immunocompromisedThe immunocompromised

To what phylum do the causes of superficial fungal To what phylum do the causes of superficial fungal infections of skin, nails, and soft tissues belong? What infections of skin, nails, and soft tissues belong? What species are common?species are common?– Ascomycotina Ascomycotina – Trichophyton, MicrosporumTrichophyton, Microsporum

What phylum causes thrush?What phylum causes thrush?– Deuteromycotina (e.g. Candida Albicans)Deuteromycotina (e.g. Candida Albicans)

Which two phyla cause systemic fungal infections?Which two phyla cause systemic fungal infections?– Zygomycotina (Rhizopus nigrans) and basidiomycotina Zygomycotina (Rhizopus nigrans) and basidiomycotina

(cryptococcus, histoplasmosis)(cryptococcus, histoplasmosis)

Page 3: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

PolyenesPolyenesWhat are the 2 distinct portions of amphotercin B?What are the 2 distinct portions of amphotercin B?– Hydrophobic MacrolideHydrophobic Macrolide– Polyene (7 trans double bonds)Polyene (7 trans double bonds)

How does amphotericin B work?How does amphotericin B work?– Hydrophobic portion binds to ergosterol in fungal cell membrane and Hydrophobic portion binds to ergosterol in fungal cell membrane and

forms a pore. This causes ion leakage, disrupts cellular metabolism, forms a pore. This causes ion leakage, disrupts cellular metabolism, and enhances cell mediated immunity.and enhances cell mediated immunity.

What two ions are leaked out of the pore?What two ions are leaked out of the pore?– KK++ and Mg and Mg++++

Why doesn’t amphotericin B put holes in human cells?Why doesn’t amphotericin B put holes in human cells?– Human cells contain Cholesterol, while fungal cells contain Human cells contain Cholesterol, while fungal cells contain

Ergosterol. This explains the selectivity. Ergosterol. This explains the selectivity.

Is resistance a problem?Is resistance a problem?– Not right now, but it could occur in the future with mutants with Not right now, but it could occur in the future with mutants with

decreased concentrations of membrane ergosterol.decreased concentrations of membrane ergosterol.

Page 4: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

Amphoterrible continuedAmphoterrible continued

How water soluble and orally available is Amphotericin B?How water soluble and orally available is Amphotericin B?– It is water insoluble, absorption is negligible, and it is 90% protein bound. It is water insoluble, absorption is negligible, and it is 90% protein bound.

How do you get a water insoluble solution in IV?How do you get a water insoluble solution in IV?– Complex it with Bile salt deoxycholate (Complex it with Bile salt deoxycholate (0.4 microns colloid/micelles).0.4 microns colloid/micelles).

What are the adverse effects of Amphotercin B?What are the adverse effects of Amphotercin B?– Fever and Chills, Fever and Chills, Nephrotoxic, Nephrotoxic, anemia, and rare neurotoxicity and anemia, and rare neurotoxicity and

hypersensitivity.hypersensitivity.What is good about the new amphotercin B formulation?What is good about the new amphotercin B formulation?– It’s a lipid reservoirIt’s a lipid reservoir– Decreases in Nephotoxicity. However, its cost is prohibitive.Decreases in Nephotoxicity. However, its cost is prohibitive.

What is the dose range for Amphotericin B?What is the dose range for Amphotericin B?– 0.2- 1.2 mg/kg/day0.2- 1.2 mg/kg/day

What is its main therapeutic use?What is its main therapeutic use?– It is the treatment of choice (IV) for nearly all life threatening mycotic It is the treatment of choice (IV) for nearly all life threatening mycotic

infections. infections. – Broad spectrum. Can be taken orally or topically for Candida.Broad spectrum. Can be taken orally or topically for Candida.

Page 5: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

Nystatin and FlucytosineNystatin and FlucytosineWhy can’t you use nystatin systemically?Why can’t you use nystatin systemically?– It’s too toxic.It’s too toxic.

How well is nystatin absorbed?How well is nystatin absorbed?– It isn’t absorbed from the GI tract, skin, or vagina. It isn’t absorbed from the GI tract, skin, or vagina.

What are the therapeutic uses?What are the therapeutic uses?– Orally: swish and swallow for candidaOrally: swish and swallow for candida– Vaginally: insert or cream for candidaVaginally: insert or cream for candida

What is important to remember about Fluctytosine?What is important to remember about Fluctytosine?– Resistance develops very quickly when you use this drug alone. Resistance develops very quickly when you use this drug alone. – Never use alone!!!Never use alone!!!

What is the mechanism of flucytosine?What is the mechanism of flucytosine?– In the fungal cell, flucytosine is converted to 5FU, which inhibitis In the fungal cell, flucytosine is converted to 5FU, which inhibitis

thymidylate synthesis, which interferes with DNA synthesis.thymidylate synthesis, which interferes with DNA synthesis.– Mammals do not convert flucytosine to 5FU, thus are unaffected.Mammals do not convert flucytosine to 5FU, thus are unaffected.

Page 6: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

Flucytosine continuedFlucytosine continued

Describe the pharmacokinetics of Fucytosine.Describe the pharmacokinetics of Fucytosine.– It is very different from previously covered anti-fungals It is very different from previously covered anti-fungals

in that it is well absorbed from the GI tract, crosses in that it is well absorbed from the GI tract, crosses the blood-brain-barrier, is widely distributed in the the blood-brain-barrier, is widely distributed in the body, and is minimally bound to plasma proteinsbody, and is minimally bound to plasma proteins

– Half life is 3-6 hoursHalf life is 3-6 hours

What are the adverse effects of flucytosine?What are the adverse effects of flucytosine?– Bone marrow suppression, elevation of hepatic Bone marrow suppression, elevation of hepatic

enzymes (5% of patients)enzymes (5% of patients)

For what is flucytosine used?For what is flucytosine used?– Often combined with amphotericin B, the treatment of Often combined with amphotericin B, the treatment of

choice for cryptococcal and candida meningitischoice for cryptococcal and candida meningitis

Page 7: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

Imidazoles and TriazolesImidazoles and Triazoles

What is an imidazole?What is an imidazole?– More toxic compound with 2 nitrogen azole ringsMore toxic compound with 2 nitrogen azole rings

What is a triazole?What is a triazole?– Less toxic with 3 nitrogen azole ringsLess toxic with 3 nitrogen azole rings

What is the mechanism of all imidazoles and triazoles?What is the mechanism of all imidazoles and triazoles?– Inhibits sterol 14-Inhibits sterol 14-αα-demethylase which is involved in formation of ergosterol. -demethylase which is involved in formation of ergosterol.

This inhibition leads to an accumulation of 14-a-methyl sterols.This inhibition leads to an accumulation of 14-a-methyl sterols.What are the important things to know about ketoconazole—Class, What are the important things to know about ketoconazole—Class, absorption, distribution, adverse effects, drug interactions, onset of absorption, distribution, adverse effects, drug interactions, onset of action, half life?action, half life?– It’s an It’s an imidazoleimidazole– It is absorbed well from GI tract.It is absorbed well from GI tract.– Widely distributed but doesn’t cross the BBBWidely distributed but doesn’t cross the BBB– Endocrine abnormalities are the most troubling side effects.Endocrine abnormalities are the most troubling side effects.

Gynecomastia and others.Gynecomastia and others.– H2 blockers reduce their absorption by reducing acidic environment.H2 blockers reduce their absorption by reducing acidic environment.– Slow response time…contraindicated in rapidly progressing fungal Slow response time…contraindicated in rapidly progressing fungal

infections.infections.– Half life is 8 hours.Half life is 8 hours.

Page 8: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

Fluconazole and ItraconazoleFluconazole and ItraconazoleWhat is different with Fluconazole (from ketoconazole)?What is different with Fluconazole (from ketoconazole)?– It’s a triazoleIt’s a triazole– Crosses BBBCrosses BBB– Greater GI absorption, longer half life (24 hours)Greater GI absorption, longer half life (24 hours)– No adverse endocrine effectsNo adverse endocrine effects

What are some therapeutic uses for Fluconazole?What are some therapeutic uses for Fluconazole?– Treatment of choice for preventing relapse following successful treatment of Treatment of choice for preventing relapse following successful treatment of

cryptococcal meningitis with Amphotericin B.cryptococcal meningitis with Amphotericin B.– Vaginal candidiasis?Vaginal candidiasis?– Prophylactic and acute treatment of oral and esophageal candidiasis in AIDSProphylactic and acute treatment of oral and esophageal candidiasis in AIDS

What is Itraconazole?What is Itraconazole?– A newer more expensive antifungal drugA newer more expensive antifungal drug– Less toxic than ketoconazole and has a broader spectrum, but doesn’t cross Less toxic than ketoconazole and has a broader spectrum, but doesn’t cross

BBB.BBB.What are clotrimazole and miconazole used for?What are clotrimazole and miconazole used for?– These older imidazoles are used topically to treat various fungal infections. These older imidazoles are used topically to treat various fungal infections.

They are too toxic for systemic use.They are too toxic for systemic use.

Page 9: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

GriseofulvinGriseofulvinWhat is the MOA of Griseofulvin?What is the MOA of Griseofulvin?– Inhibits fungal mitosis by producing multinucleated cells. Disrupts Inhibits fungal mitosis by producing multinucleated cells. Disrupts

mitotic spindle by interacting with polymerized microtubules.mitotic spindle by interacting with polymerized microtubules.– FungistaticFungistatic

How is Griseofulvin adminstered?How is Griseofulvin adminstered?– Orally administered and absorbed from the GI tractOrally administered and absorbed from the GI tract

What happens at high doses?What happens at high doses?– Will affect mammalian cells. Will affect mammalian cells. – “…“…selectivity of action is determined by highest tissue concentration.”selectivity of action is determined by highest tissue concentration.”

What is the disadvantage of Griseofulvin?What is the disadvantage of Griseofulvin?– Prolonged treatment required. Up to a Year!Prolonged treatment required. Up to a Year!

What are the therapeutic uses?What are the therapeutic uses?– Griseofulvin is administered orally to treat mycotic infections of skin, hair Griseofulvin is administered orally to treat mycotic infections of skin, hair

and nails caused by microsporum, trichophyton, and epidermophyton, and nails caused by microsporum, trichophyton, and epidermophyton, but but not candidanot candida..

What adverse effects are noted with Griseofulvin?What adverse effects are noted with Griseofulvin?– Headache, lethargy, confusion, ethanol potentiation, rashes, liver Headache, lethargy, confusion, ethanol potentiation, rashes, liver

enzyme induction, teratogen and carcinogen.enzyme induction, teratogen and carcinogen.

Page 10: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

TerbinafineTerbinafine

What is the MOA of Terbinafine?What is the MOA of Terbinafine?– Inhibition of squalene epoxidase leading to Inhibition of squalene epoxidase leading to

accumulation of sterol squalene, which is accumulation of sterol squalene, which is toxic to the organism.toxic to the organism.

– FungicidalFungicidal

What is the advantage of Terbinafine What is the advantage of Terbinafine compared to Griseofulvin?compared to Griseofulvin?– Only have to take it up to 12 weeks, “more Only have to take it up to 12 weeks, “more

effective than griseofulvin.”effective than griseofulvin.”

Page 11: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

Gastric Acid ProductionGastric Acid Production

Page 12: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

Intro to these three lecturesIntro to these three lectures

There will be 5 questions from gastric acidity, 2 There will be 5 questions from gastric acidity, 2 GI questions, and 2 Nausea/Vomiting questions.GI questions, and 2 Nausea/Vomiting questions.What are the proton pump inhibitors?What are the proton pump inhibitors?– They end in –prazole. Omeprazole, lansoprazole, They end in –prazole. Omeprazole, lansoprazole,

rabeprazole, pantoprazole, esomeprazolerabeprazole, pantoprazole, esomeprazole

What are the H2 receptor antagonists?What are the H2 receptor antagonists?– Cimetidine, ranitidine, famotidine, nizatidine.Cimetidine, ranitidine, famotidine, nizatidine.– They end in -tidineThey end in -tidine

What are the antacids?What are the antacids?– Sodium bicarbonate, calcium carbonate, MgSodium bicarbonate, calcium carbonate, Mg++++, ,

Aluminum compounds, and mixturesAluminum compounds, and mixtures

Page 13: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

Acidity DiseasesAcidity Diseases

What are the GI diseases and disorders related to What are the GI diseases and disorders related to GI acid production (4)?GI acid production (4)?– Dyspepsia, acid indigestion, “heartburn”Dyspepsia, acid indigestion, “heartburn”– Gastroesophageal reflux diseaseGastroesophageal reflux disease

The difference b/w GERD and heartburn is that GERD is The difference b/w GERD and heartburn is that GERD is recurrent and includes major reflux to such an extent that it can recurrent and includes major reflux to such an extent that it can actually cause esophagitis. GERD is due to a relaxed LES. actually cause esophagitis. GERD is due to a relaxed LES.

– Gastric and duodenal ulcersGastric and duodenal ulcers– Zollinger-Ellison syndrome (excess gastrin secretion) and Zollinger-Ellison syndrome (excess gastrin secretion) and

hypersecretory states (involve overproduction of gastrin) hypersecretory states (involve overproduction of gastrin)

What two receptors are present on the What two receptors are present on the enterochromafin-like cell that increase that cells enterochromafin-like cell that increase that cells release of gastrin?release of gastrin?– Histamine type 2 and Muscarinic type 1 receptorsHistamine type 2 and Muscarinic type 1 receptors

Page 14: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

EsophagitisEsophagitisWhy do we get acid into the esophagus?Why do we get acid into the esophagus?– Relaxed LESRelaxed LES

What are three ways to modulate acid-induced disease?What are three ways to modulate acid-induced disease?– Inhibit acid secretionInhibit acid secretion– Protect GI mucosaProtect GI mucosa– Neutralize the acid that is secretedNeutralize the acid that is secreted

What does gastrin do?What does gastrin do?– It activates the release of histamine from ECL (Enterochromafin-like) cell. The It activates the release of histamine from ECL (Enterochromafin-like) cell. The

histamine will then bind to an H2 receptor on the parietal cell. This produces a rise in histamine will then bind to an H2 receptor on the parietal cell. This produces a rise in cAMP and activates the proton pump to secrete HcAMP and activates the proton pump to secrete H++..

With what is Helicobacter pylori associated? When does infection occur?With what is Helicobacter pylori associated? When does infection occur?– Gastric cancer, Gastric/duodenal ulcers, and gastric Gastric cancer, Gastric/duodenal ulcers, and gastric B cell lymphomaB cell lymphoma..– Infection is typically acquired in childhood.Infection is typically acquired in childhood.

How is it passed from person to person?How is it passed from person to person?– We really don’t know. Maybe oral to oral or fecal-oralWe really don’t know. Maybe oral to oral or fecal-oral

What are the diagnostic tests for H. pylori?What are the diagnostic tests for H. pylori?– Serology, urease breath test, fecal antigen test, endoscopy (expensive/invasive)Serology, urease breath test, fecal antigen test, endoscopy (expensive/invasive)

Page 15: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

Proton Pump InhibitorsProton Pump InhibitorsWhat is the mechanism of action of the proton pump inhibitors (PPIs)?What is the mechanism of action of the proton pump inhibitors (PPIs)?– suicide inhibitor of the H+/K+-ATPase (interacts covalently) suicide inhibitor of the H+/K+-ATPase (interacts covalently) – Recovery requires synthesis of new enzyme and insertion into the parietal Recovery requires synthesis of new enzyme and insertion into the parietal

cell membrane; this is why they are long-acting drugs; administered in cell membrane; this is why they are long-acting drugs; administered in delayed-release, gelatin-coated capsules, or enteric-coated granules, or delayed-release, gelatin-coated capsules, or enteric-coated granules, or enteric-coated tables, or powered drug with sodium bicarbonate. enteric-coated tables, or powered drug with sodium bicarbonate.

– They are activated in the presence of acid, where they are protonated. They are activated in the presence of acid, where they are protonated. Once protonated, the drug is able to react with a free Once protonated, the drug is able to react with a free unpaired cysteineunpaired cysteine in in the proton pump.the proton pump.

What is the half life of the ppi drugs?What is the half life of the ppi drugs?– 30-90 minutes, but duration of action can be all day (until new enzyme is 30-90 minutes, but duration of action can be all day (until new enzyme is

synthesized).synthesized).When should PPI drugs be taken?When should PPI drugs be taken?– Before a meal (on an empty stomach with high acidity); they are absorbed Before a meal (on an empty stomach with high acidity); they are absorbed

better at this time.better at this time.For what conditions are PPI drugs recommended?For what conditions are PPI drugs recommended?– Peptic ulcer disease, dyspepsia, GERD, Zollinger-Ellison syndrome, NSAID Peptic ulcer disease, dyspepsia, GERD, Zollinger-Ellison syndrome, NSAID

induced ulcerinduced ulcer

Page 16: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

Proton Pump InhibitingProton Pump Inhibiting

What is the difference between esomeprazole and omeprazole? Which one is What is the difference between esomeprazole and omeprazole? Which one is more effective?more effective?– Esomeprazole is the purified S isomer of omeprazole (which is mixed R-and S-Esomeprazole is the purified S isomer of omeprazole (which is mixed R-and S-

isomer); this is Nexium; the little pharmacological difference is that maybe there isomer); this is Nexium; the little pharmacological difference is that maybe there is a little less first-pass metabolism. is a little less first-pass metabolism.

– They are equally effective.They are equally effective.What is the treatment of choice for H. pylori positive gastric/duodenal ulcer What is the treatment of choice for H. pylori positive gastric/duodenal ulcer disease? What other drug combination is available? disease? What other drug combination is available? – Amoxicillin and Clarithromycin are most effective in addition to a PPI Amoxicillin and Clarithromycin are most effective in addition to a PPI

(omeprazole, for instance). (omeprazole, for instance). – The other combination is PPI + bismuth subsalicylate + tetracycline + The other combination is PPI + bismuth subsalicylate + tetracycline +

metronidazole metronidazole These two 10-14 day treatment options are considered “permanent” ulcer cures.These two 10-14 day treatment options are considered “permanent” ulcer cures.

How do you treat an NSAID-induced ulcer?How do you treat an NSAID-induced ulcer?– use PPIs and reduce, eliminate, or change the NSDAIDs. use PPIs and reduce, eliminate, or change the NSDAIDs.

What side effects are noticed with PPIs?What side effects are noticed with PPIs?– Rarely nausea, diarrhea, headache, dizziness, bacterial overgrowth in stomach.Rarely nausea, diarrhea, headache, dizziness, bacterial overgrowth in stomach.– New research indicates increased risk of hip fracture in elderly patients on long-New research indicates increased risk of hip fracture in elderly patients on long-

term high-dose PPI therapyterm high-dose PPI therapy

Page 17: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

ComparasizingComparasizing

Compare HCompare H22 blockers to PPI drugs. blockers to PPI drugs.– HH22 blockers are used for the same indications as blockers are used for the same indications as

PPIs; they’re not as effective, but they’re great for PPIs; they’re not as effective, but they’re great for people with average acid dyspepsia. These act by people with average acid dyspepsia. These act by blocking Hblocking H2 2 receptors on parietal cells. receptors on parietal cells.

– PPI drugs are better at everythingPPI drugs are better at everything

Contrast the metabolism of PPIs to HContrast the metabolism of PPIs to H22 blockers. blockers.– While PPIs are metabolized by the liver, HWhile PPIs are metabolized by the liver, H22 blockers blockers

are excreted unchanged by the kidney. Thus these are excreted unchanged by the kidney. Thus these drugs should not be given to patients with severe drugs should not be given to patients with severe renal impairment.renal impairment.

Page 18: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

AlternativesAlternativesAre the PPIs as effective as the H2 antagonists at healing esophagitis?Are the PPIs as effective as the H2 antagonists at healing esophagitis?– PPIs are more effective than H2 antagonists at both relieving symptoms and PPIs are more effective than H2 antagonists at both relieving symptoms and

healing esophagitis.healing esophagitis.By what CYPs are PPIs metabolized? Which one is least metabolized?By what CYPs are PPIs metabolized? Which one is least metabolized?– PPIs are metabolized by CYP2C19PPIs are metabolized by CYP2C19– rabeprazole is the least metabolized rabeprazole is the least metabolized

What percentage of people on H2 antagonists report side effects? What percentage of people on H2 antagonists report side effects? Which H2 antagonist has anti-androgenic activity?Which H2 antagonist has anti-androgenic activity?– Less than 3%, sometimes less than placebo patients.Less than 3%, sometimes less than placebo patients.– cimetidinecimetidine

What are the antimuscarinics? What is their mechanism? Why don’t What are the antimuscarinics? What is their mechanism? Why don’t we use them much?we use them much?– Pirenzepine, telenzipinePirenzepine, telenzipine– Block M1 action in gangliaBlock M1 action in ganglia– Their autonomic side effects are much worse than other choices for reducing Their autonomic side effects are much worse than other choices for reducing

acid productionacid productionWhat are the mucosal protective agents?What are the mucosal protective agents?– Sucralfate (carafate), misoprostol (Cytotec)Sucralfate (carafate), misoprostol (Cytotec)

Page 19: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

Sucralfate, Misprostol, BismuthSucralfate, Misprostol, Bismuth

What is the mechanism of Sucralfate? What are its side effects and drug What is the mechanism of Sucralfate? What are its side effects and drug interactions? interactions? – complex alumninum-sucrose sulfate; complex alumninum-sucrose sulfate; – Sucralfate is thought to coat ulcer, acting as an acid/pepsin barrier; it binds Sucralfate is thought to coat ulcer, acting as an acid/pepsin barrier; it binds

preferentially to the ulcer. It has no anti-acid effect but may stimulate PGE synthesis; preferentially to the ulcer. It has no anti-acid effect but may stimulate PGE synthesis; activated by acidic environmentactivated by acidic environment

– few- dry mouth, constipation, decreased bioavailability of TCN, phenytoin, digoxin, few- dry mouth, constipation, decreased bioavailability of TCN, phenytoin, digoxin, cimetidinecimetidine

What is the mechanism of Misoprostol? What is the main problem with What is the mechanism of Misoprostol? What is the main problem with misoprostol?misoprostol?– Synthetic analog of PGE1; PGs decrease gastric secretion and increase mucus and Synthetic analog of PGE1; PGs decrease gastric secretion and increase mucus and

bicarbonate secretion.bicarbonate secretion.aspirin-like drugs decrease PGs and increase ulcer incidence. aspirin-like drugs decrease PGs and increase ulcer incidence.

– This drug works elsewhere in the body to contract smooth muscle. (contraindicated in This drug works elsewhere in the body to contract smooth muscle. (contraindicated in pregnancy)pregnancy)

Name the colloidal bismuth compounds. What is their mechanism?Name the colloidal bismuth compounds. What is their mechanism?– Bismuth subgallate, subcitrate, subnitrate, subsalicylate (most common here; Bismuth subgallate, subcitrate, subnitrate, subsalicylate (most common here;

PeptoBismol)PeptoBismol)– Increase mucosal secretion, coat ulcer, thus cytoprotection. Cause detachment of H. Increase mucosal secretion, coat ulcer, thus cytoprotection. Cause detachment of H.

pylori from gastric epithelium and lysis of bacterium. Not approved alone for peptic pylori from gastric epithelium and lysis of bacterium. Not approved alone for peptic ulcer, no acid-neutralizing activity but does inhibit secretion of gastrin.ulcer, no acid-neutralizing activity but does inhibit secretion of gastrin.

Page 20: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

Antacids 1Antacids 1What are the antacids? Can they heal a peptic ulcer? What What are the antacids? Can they heal a peptic ulcer? What side effects are common?side effects are common?– Bases that react with stomach acid and neutralize it: Bases that react with stomach acid and neutralize it:

Baking soda (NaHCOBaking soda (NaHCO33), Milk of Magneisa, Calcium Carbonate (CaCO), Milk of Magneisa, Calcium Carbonate (CaCO33), ), Aluminum compounds, and mixtures.Aluminum compounds, and mixtures.

– They can heal an ulcer if dosed often enough.They can heal an ulcer if dosed often enough.– Alkaluria, high Na+ content in some.Alkaluria, high Na+ content in some.

What are the uses for the antacids? What are the uses for the antacids? – peptic ulcer, GERD, occasional heartburnpeptic ulcer, GERD, occasional heartburn

What is the basic mechanism of antacids?What is the basic mechanism of antacids?– bases present in the antacid react with an neutralize stomach acid; bases present in the antacid react with an neutralize stomach acid;

decreases symptoms of heartburn and acid-induced paindecreases symptoms of heartburn and acid-induced pain

What general side effects are common with antacids?What general side effects are common with antacids?– alkaluria- may cause kidney stones; sodium content may be high in alkaluria- may cause kidney stones; sodium content may be high in

some preparations, which is dangerous in CHF.some preparations, which is dangerous in CHF.

Page 21: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

Antacids 2Antacids 2Why is baking soda not the best antacid?Why is baking soda not the best antacid?– NaHCONaHCO33 (baking soda) is a highly soluble base that reacts quickly with acid (baking soda) is a highly soluble base that reacts quickly with acid

and is absorbed completely. It can cause transient metabolic alkalosis as and is absorbed completely. It can cause transient metabolic alkalosis as well as fluid retention due to a very high sodium load. It has a very short well as fluid retention due to a very high sodium load. It has a very short length of action.length of action.

This is bad.This is bad.

What is the chemical makeup of Tums?What is the chemical makeup of Tums?– Calcium carbonate (CaCOCalcium carbonate (CaCO33) tums. A decent antacid, not well absorbed. It is ) tums. A decent antacid, not well absorbed. It is

often recommended for women with occasional dyspepsia with the rationale often recommended for women with occasional dyspepsia with the rationale that the Cathat the Ca++++ is inherently helpful. Hypercalcemia can be a problem in is inherently helpful. Hypercalcemia can be a problem in patients with very poor renal function.patients with very poor renal function.

How does milk of magnesia work and what is its primary side effect?How does milk of magnesia work and what is its primary side effect?– Milk of magnesia (magnesium salts) reacts rapidly with HCl, has a slower Milk of magnesia (magnesium salts) reacts rapidly with HCl, has a slower

rate of emptying from the stomach. Mg ion is poorly absorbed but does rate of emptying from the stomach. Mg ion is poorly absorbed but does have osmotic effect and can pull water into the gastric lumen, causing have osmotic effect and can pull water into the gastric lumen, causing diarrhea.diarrhea.

What is the down side of Aluminum antacids?What is the down side of Aluminum antacids?– Aluminum compounds are very effective but cause constipation.Aluminum compounds are very effective but cause constipation.

What are the best antacids?What are the best antacids?– Antacid mixtures of magnesium and aluminum salts are the best antacids: Antacid mixtures of magnesium and aluminum salts are the best antacids:

Maalox and Mylanta (best).Maalox and Mylanta (best).

Page 22: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

Gastric MotilityGastric Motility

Page 23: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

Motility and ConstipationMotility and Constipation

What happens when the myenteric plexus is activated?What happens when the myenteric plexus is activated?– Increases tonic contraction, increases intensity and rate of contractions, Increases tonic contraction, increases intensity and rate of contractions,

increases velocity of contractionsincreases velocity of contractionsThe myenteric plexus also promotes release of excitatory mediators The myenteric plexus also promotes release of excitatory mediators proximally (contraction). What are they (3)?proximally (contraction). What are they (3)?– acetylcholine (muscarinic M2 and M3 receptors on GI smooth muscle)acetylcholine (muscarinic M2 and M3 receptors on GI smooth muscle)– serotonin (5-HT3 and 5-HT4 serotonin receptors)serotonin (5-HT3 and 5-HT4 serotonin receptors)– neuropeptides neuropeptides

How might mild consipation be treated in an otherwise healthy person?How might mild consipation be treated in an otherwise healthy person?– no medication needed; increase intake of fiber, fruits, vegetables, complex no medication needed; increase intake of fiber, fruits, vegetables, complex

carbs, bran; exercise; adequate fluid intakecarbs, bran; exercise; adequate fluid intakelaxative administration is appropriate for what?laxative administration is appropriate for what?– prevention of straining in patients with hernia, hemorrhoidsprevention of straining in patients with hernia, hemorrhoids– evacuation of bowel before surgery, colon procedures (endoscopy)evacuation of bowel before surgery, colon procedures (endoscopy)

What drugs cause constipation?What drugs cause constipation?– drugs causing constipation include phenothiazines, anticholinergics, Ca/Al drugs causing constipation include phenothiazines, anticholinergics, Ca/Al

antacids, and antidiarrheal agents.antacids, and antidiarrheal agents.

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Anti-constipants Anti-constipants What are the bulk laxative agents? What effect do they have?What are the bulk laxative agents? What effect do they have?– hydrophilic colloids, psyllium (Metamucil, Per Diem, many others), agar, hydrophilic colloids, psyllium (Metamucil, Per Diem, many others), agar,

bran, methylcellulosebran, methylcellulose– indigestable plant products; dietary fiber and supplements – absorb water indigestable plant products; dietary fiber and supplements – absorb water

and distend the colon, promoting peristalsis. They may increase bloating and and distend the colon, promoting peristalsis. They may increase bloating and gas.gas.

first line for chronic constipationfirst line for chronic constipation

What are the osmotic agent laxatives? How do they work?What are the osmotic agent laxatives? How do they work?– Any poorly absorbed ion. There are saline cathartics, Mg(OH)Any poorly absorbed ion. There are saline cathartics, Mg(OH)22, MgSO, MgSO44, ,

sorbitol, laculose, polyethylene glycol.sorbitol, laculose, polyethylene glycol.– These unabsorbed ions pull water into the gut by osmosis. The increased These unabsorbed ions pull water into the gut by osmosis. The increased

water distends the bowel and stimulates peristaltic contractions.water distends the bowel and stimulates peristaltic contractions.What are the stool softeners and how do they work?What are the stool softeners and how do they work?– Glycerin and docusate. They allow water to penetrate the stool.Glycerin and docusate. They allow water to penetrate the stool.

What are the stimulant laxatives?What are the stimulant laxatives?– Anthraquinones- aloe, senna, cascaraAnthraquinones- aloe, senna, cascara

What is the serotonin-4 receptor agonist laxative? How does it work What is the serotonin-4 receptor agonist laxative? How does it work and for what is it (primarily) used?and for what is it (primarily) used?– TegaserodTegaserod– Used to activate myenteric plexus and peristalsis, particularly in irritable Used to activate myenteric plexus and peristalsis, particularly in irritable

bowel syndrome.bowel syndrome.

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More constipantagonistsMore constipantagonistsWhat is the cholinomimetic agent laxative? How does it work? For what What is the cholinomimetic agent laxative? How does it work? For what (specifically) is it used?(specifically) is it used?– Neostigmine (AchE inhibitor). Neostigmine (AchE inhibitor). – Enhance gastric, duodenal, and colonic emptying (M3 activation). Has lots of side Enhance gastric, duodenal, and colonic emptying (M3 activation). Has lots of side

effects.effects.– Useful for acute large bowel distention.Useful for acute large bowel distention.

What are the D2 antagonists? How do they work? For what are they primarily What are the D2 antagonists? How do they work? For what are they primarily used?used?– metoclopramide and domperidonemetoclopramide and domperidone– D2 antagonists inhibit dopamine’s inhibition of cholinergic action.D2 antagonists inhibit dopamine’s inhibition of cholinergic action.

increase peristaltic amplitude, increase lower esophageal sphincter pressure, enhance increase peristaltic amplitude, increase lower esophageal sphincter pressure, enhance gastric emptying, decrease transit timegastric emptying, decrease transit time

– mostly used as anti-emeticsmostly used as anti-emeticsHow do macrolides work?How do macrolides work?– Stimulate motilin receptors on G-I smooth muscle (erythromycin). Rapid tolerance Stimulate motilin receptors on G-I smooth muscle (erythromycin). Rapid tolerance

develops.develops.Remember ole Dr. Melchert suffering under these drugs because his mom thought he was Remember ole Dr. Melchert suffering under these drugs because his mom thought he was allergic to penacillin.allergic to penacillin.

What is the chloride channel activators? What is its mechanism? What is the chloride channel activators? What is its mechanism? – lubiprostone – recently approved for chronic constipationlubiprostone – recently approved for chronic constipation– increases liquid secretion into the lumen and shortens transit timeincreases liquid secretion into the lumen and shortens transit time

What is the emphasis in the time you put in this material?What is the emphasis in the time you put in this material?– ““should really be with uses of these drugs and what category it falls under”should really be with uses of these drugs and what category it falls under”

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D2 Antagonists and OpioidsD2 Antagonists and OpioidsHow do the D2 antagonists work?How do the D2 antagonists work?– D2 receptor blocks acetylcholine release. Blocking D2 stimulates Ach release. D2 receptor blocks acetylcholine release. Blocking D2 stimulates Ach release.

Stimulating Ach release increases motility.Stimulating Ach release increases motility.How does Bismuth subsalicylate reduce diarrhea? What other good anti-How does Bismuth subsalicylate reduce diarrhea? What other good anti-diarrheal action does it have (microbiologically)? What are its side effects?diarrheal action does it have (microbiologically)? What are its side effects?– inflammatory prostaglandins stimulate diarrhea, inhibitors of cycloxygenase are inflammatory prostaglandins stimulate diarrhea, inhibitors of cycloxygenase are

antimotilityantimotilitySubsalicylate is a mild COX inhibitorSubsalicylate is a mild COX inhibitor

– may prevent colonization with foreign may prevent colonization with foreign E. coliE. coli (prevents bacterial binding to mucosa) (prevents bacterial binding to mucosa) providing protection from traveller’s diarrhea.providing protection from traveller’s diarrhea.

– constipating, tinnitusconstipating, tinnitusWhat opioids are used for control of diarrhea? How do they work? What opioids are used for control of diarrhea? How do they work? – Diphenoxylate and loperamideDiphenoxylate and loperamide– Like all opioids, these drugs inhibit pre-synaptic cholinergic neurons in the Like all opioids, these drugs inhibit pre-synaptic cholinergic neurons in the

submucosal and myeteric plexus, which causes increased segmental contractions, submucosal and myeteric plexus, which causes increased segmental contractions, decreased propulsive peristalsis, increased transit time, decreased secretions from decreased propulsive peristalsis, increased transit time, decreased secretions from stomach, pancreas, and intestine, delayed digestion, and increased absorption of Na stomach, pancreas, and intestine, delayed digestion, and increased absorption of Na and water.and water.

What are the agents in Lomotil?What are the agents in Lomotil?– Diphenoxylate and atropine. The atropine is added mainly to prevent abuse.Diphenoxylate and atropine. The atropine is added mainly to prevent abuse.

Why isn’t loperamide addictive?Why isn’t loperamide addictive?– It does not cross the blood brain barrier.It does not cross the blood brain barrier.

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Irritable DrugsIrritable DrugsWhat is Irritable Bowel Syndrome?What is Irritable Bowel Syndrome?– IBS is an idopathic chronic relapsing disorder characterized by abdominal IBS is an idopathic chronic relapsing disorder characterized by abdominal

discomfort (pain, bloating, distension or cramps) in association with alterations discomfort (pain, bloating, distension or cramps) in association with alterations in bowel habits (diarrhea, constipation or both). Patients note a change in in bowel habits (diarrhea, constipation or both). Patients note a change in frequency or consistency of their bowel movements.frequency or consistency of their bowel movements.

Do people with irritable bowel syndrome have constipation or diarrhea?Do people with irritable bowel syndrome have constipation or diarrhea?– They might have either one. It varies from patient to patient and day to day.They might have either one. It varies from patient to patient and day to day.

What is the main drug used for irritable bowel syndrome? How does this What is the main drug used for irritable bowel syndrome? How does this drug work?drug work?– AlosetronAlosetron– It is a Serotonin-3 antagonist; 5-HTIt is a Serotonin-3 antagonist; 5-HT33 receptors are prevalent on receptors are prevalent on

enterochromaffin cells and they mediate bowel induced pain. Also, 5-HT3 enterochromaffin cells and they mediate bowel induced pain. Also, 5-HT3 receptors exist on enteric cholinergic neurons. Blockade of these receptors receptors exist on enteric cholinergic neurons. Blockade of these receptors inhibits colonic motility. inhibits colonic motility.

What other drug is good for predominantly constipated IBS? How does it What other drug is good for predominantly constipated IBS? How does it work?work?– Tegaserod is good for predominantly constipated IBS.Tegaserod is good for predominantly constipated IBS.– Tegaserod is a 5-HTTegaserod is a 5-HT44 agonist agonist

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Nausea and VomitingNausea and Vomiting

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ObjectivesObjectives

““At the end of this lecture, you should be able to:At the end of this lecture, you should be able to:– Understand the mechanism(s) that control nausea Understand the mechanism(s) that control nausea

and vomiting.and vomiting.– List drugs used in the prevention of List drugs used in the prevention of

chemotherapy/radiation-induced nausea and vomiting chemotherapy/radiation-induced nausea and vomiting and describe their mechanism of action.and describe their mechanism of action.

– List drugs used in the prevention of post-operative List drugs used in the prevention of post-operative nausea and vomiting and describe their mechanisms.”nausea and vomiting and describe their mechanisms.”

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Activate UpchuckActivate Upchuck

Where is the vomiting center located? What nerves are Where is the vomiting center located? What nerves are involved in emesis triggarization? involved in emesis triggarization? – The vomiting center is located in lateral medullary reticular The vomiting center is located in lateral medullary reticular

formation, close to the fourth ventricle (brainstem)formation, close to the fourth ventricle (brainstem)– The vomiting center works through many efferents; it coordinates The vomiting center works through many efferents; it coordinates

actions with cranial nerves V, VII, IX, X and XII and spinal nerves to actions with cranial nerves V, VII, IX, X and XII and spinal nerves to G-I tract, diaphragm and abdominal musclesG-I tract, diaphragm and abdominal muscles

What triggers the vomiting center?What triggers the vomiting center?– The chemoreceptor trigger zone (CRZ), located in the 4th ventricle in The chemoreceptor trigger zone (CRZ), located in the 4th ventricle in

the area postrema. It is outside the BBB and thus accessible to the area postrema. It is outside the BBB and thus accessible to emetogenic stimuli in the blood or CSF.emetogenic stimuli in the blood or CSF.

What kind of receptors exist in the CRZ?What kind of receptors exist in the CRZ?– Although the exact mechanism is not well understood, peripheral Although the exact mechanism is not well understood, peripheral

neuroreceptors and the chemoreceptor trigger zone (CRZ) are neuroreceptors and the chemoreceptor trigger zone (CRZ) are known to possess receptors for serotonin, histamine (H1 and H2), known to possess receptors for serotonin, histamine (H1 and H2), dopamine, acetylcholine, opioids, and other dopamine, acetylcholine, opioids, and other neurotransmitters/neuromodulators. neurotransmitters/neuromodulators.

– rich in dopamine D2, serotonin 5-HT3 and opioid receptorsrich in dopamine D2, serotonin 5-HT3 and opioid receptors

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All the Anti-emetics on one slideAll the Anti-emetics on one slideWhat are the Serotonin-3 receptor antagonists? For what type of emesis do What are the Serotonin-3 receptor antagonists? For what type of emesis do they work?they work?– Ondansetron, granisetron, dolasetronOndansetron, granisetron, dolasetron– They work on vegal stimulated emesis (surgery, chemotherapy, and radiation)They work on vegal stimulated emesis (surgery, chemotherapy, and radiation)

Name the D2 antagonists.Name the D2 antagonists.– Metaclopramide, prochlorperazine, promethazine, droperidolMetaclopramide, prochlorperazine, promethazine, droperidol

Name the antihistamines used for anti-emesis.Name the antihistamines used for anti-emesis.– Cyclizine and meclazine, Cyclizine and meclazine,

Name the antimuscarinic agent used for motion sickness.Name the antimuscarinic agent used for motion sickness.– ScopolamineScopolamine

Name the cannabinoid used for appetite stimulation and anti-emesis in Name the cannabinoid used for appetite stimulation and anti-emesis in chemotherapy.chemotherapy.– DronabinolDronabinol

What is the name of the only neurokinin-1 antagonist for N/V?What is the name of the only neurokinin-1 antagonist for N/V?– AprepitantAprepitant

What two benzodiazepines are used for anticipatory vomiting?What two benzodiazepines are used for anticipatory vomiting?– Lorazepam and diazepamLorazepam and diazepam

What is Nick’s favorite drug of all time?What is Nick’s favorite drug of all time?– Phenergan (promethazine). Nausea sucks. Phenergan (promethazine). Nausea sucks.

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Emetified Terms Emetified Terms

Define:Define:Nausea and vomitingNausea and vomiting– A defense mechanism to remove harmful or toxic A defense mechanism to remove harmful or toxic

substancessubstances– Unpleasant sensation at back of throat, awareness of Unpleasant sensation at back of throat, awareness of

urge to vomit, cold sweat,urge to vomit, cold sweat,

RetchingRetching– The gag reflex, the labored spasmodic contractions of The gag reflex, the labored spasmodic contractions of

respiratory muscles including:respiratory muscles including:The diaphragm, chest wall, and abdominal wall muscles.The diaphragm, chest wall, and abdominal wall muscles.

– Generates pressure gradient leading to vomitingGenerates pressure gradient leading to vomiting

VomitingVomiting– Forceful expulsion of contentsForceful expulsion of contents

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Puke CentralPuke Central

Where is the vomiting center?Where is the vomiting center?– In the medulla, in the reticular formation, near to In the medulla, in the reticular formation, near to

the area postrema and chemoreceptor trigger the area postrema and chemoreceptor trigger zone zone

The chemoreceptor trigger zone is a circumventricular The chemoreceptor trigger zone is a circumventricular organ that sits outside the brain and outside the blood organ that sits outside the brain and outside the blood brain barrier, it controls the vomiting center.brain barrier, it controls the vomiting center.

– The vestibular system and balance system has The vestibular system and balance system has inputs from the cerebellum into this areainputs from the cerebellum into this area

What are some types of nausea (causes)?What are some types of nausea (causes)?– Post op, opioids, chemotherapy, preggers, Post op, opioids, chemotherapy, preggers,

motion sickness/vestibular disorders, intestinal motion sickness/vestibular disorders, intestinal infectioninfection

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Serotonin and Dopamine AntagonistsSerotonin and Dopamine Antagonists

What are the 5HT3 antagonists? What are they good for? What are the 5HT3 antagonists? What are they good for? – Ondansetron, granisetron, dolasetronOndansetron, granisetron, dolasetron– Useful to prevent emesis caused by vagal stimulation (surgery), Useful to prevent emesis caused by vagal stimulation (surgery),

chemotherapy, and radiationchemotherapy, and radiationMinimal effect on motion sickness nauseaMinimal effect on motion sickness nausea

– Well tolerated with few side effectsWell tolerated with few side effects

What are the D2 antagonists? How does each work? What What are the D2 antagonists? How does each work? What side effects (effects other than anti-emetic) are noted with side effects (effects other than anti-emetic) are noted with each?each?– MetoclopramideMetoclopramide

Central dopamine receptor blockadeCentral dopamine receptor blockadeExtrapyramidal side effects; restlessness, dystoniaExtrapyramidal side effects; restlessness, dystonia

– Prochlorperazine, promethazineProchlorperazine, promethazineInhibition of dopaminergic, muscarinic, and histaminergic receptorsInhibition of dopaminergic, muscarinic, and histaminergic receptorsSedative effect via antihistamine activitySedative effect via antihistamine activity

– DroperidolDroperidolAntiemetic via cnetral dopaminergic blockadeAntiemetic via cnetral dopaminergic blockadeAntipsychotic and sedative, can cause extrapyramidal effects and Antipsychotic and sedative, can cause extrapyramidal effects and hypotension hypotension

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Anti-emetic TypesAnti-emetic TypesWhat type of nausea are the antihistamines and anticholinergics good at What type of nausea are the antihistamines and anticholinergics good at treating? What side effects are common with these drugs?treating? What side effects are common with these drugs?– Good for motion sickness treatment, but when used alone they are weak antiemeticsGood for motion sickness treatment, but when used alone they are weak antiemetics– can cause sedation, dizziness, confusion, dry mouth, cycloplegia, urinary retentioncan cause sedation, dizziness, confusion, dry mouth, cycloplegia, urinary retention

What are cyclizine and meclizine? For what are they used?What are cyclizine and meclizine? For what are they used?– These are first generation H1 antihistamines with anticholinergic effectsThese are first generation H1 antihistamines with anticholinergic effects– Antiemetics for motion sickness or in combination with other agents for opioid and Antiemetics for motion sickness or in combination with other agents for opioid and

post-operative N & Vpost-operative N & VWhat is Scopalamine?What is Scopalamine?– An antimuscarinic (anticholinergic), it is the An antimuscarinic (anticholinergic), it is the bestbest drug for motion sickness drug for motion sickness

What is Dronabinol? For what is it used? What “adverse” effects are noted?What is Dronabinol? For what is it used? What “adverse” effects are noted?– Delta 9-tetrahydrocannabinol, marijuanaDelta 9-tetrahydrocannabinol, marijuana– A very good antiemetic and appetite stimulant, used for chemotherapyA very good antiemetic and appetite stimulant, used for chemotherapy– Can cause euphoria and dysphoria, Can cause euphoria and dysphoria,

What is the mechanism of aprepitant? It is often used in combination with what What is the mechanism of aprepitant? It is often used in combination with what other drugs?other drugs?– A Neurokinin 1 receptor antagonist (NK-1), aprepitant blocks the action of substance A Neurokinin 1 receptor antagonist (NK-1), aprepitant blocks the action of substance

P.P.– Aprepitant is often used with a 5-HTAprepitant is often used with a 5-HT33 antagonist and a corticosteroid. antagonist and a corticosteroid.

For what type of vomiting are benzodiazepines (lorazepam and diazepam) For what type of vomiting are benzodiazepines (lorazepam and diazepam) useful?useful?– Very useful in anticipatory vomiting from anxiety with chemotherapy.Very useful in anticipatory vomiting from anxiety with chemotherapy.

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Drugs for GI infectionsDrugs for GI infections

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Infectious DiarrheaInfectious DiarrheaWhy don’t we give antidiarrheals to patients with infections Why don’t we give antidiarrheals to patients with infections diarrhea?diarrhea?– They can delay clearance of microorganisms and increase risk of They can delay clearance of microorganisms and increase risk of

invasion.invasion.

What viral infections cause gastroenteritis?What viral infections cause gastroenteritis?– Rotavirus, norovirus, astroviruses, enteric adenovirus, pestivirus, Rotavirus, norovirus, astroviruses, enteric adenovirus, pestivirus,

coronavirus, enterovirusescoronavirus, enterovirusesYep, they cause it. No real treatments though.Yep, they cause it. No real treatments though.

What causes of infectious diarrhea do require treatment?What causes of infectious diarrhea do require treatment?– E. Coli (some strains?), salmonella, campylobacter jejuni, Vibrio sp., E. Coli (some strains?), salmonella, campylobacter jejuni, Vibrio sp.,

Yersinia enterocolitica (Europe), Giardia, CyclosporaYersinia enterocolitica (Europe), Giardia, CyclosporaI have no idea if any of this is “right” because there doesn’t seem to be I have no idea if any of this is “right” because there doesn’t seem to be any agreement between classes, but it sounds like pharm wins if there is any agreement between classes, but it sounds like pharm wins if there is a conflict regarding treatment.a conflict regarding treatment.

Define enterotoxigenicDefine enterotoxigenic– Secretes a toxin (which in this case produces a watery diarrhea)Secretes a toxin (which in this case produces a watery diarrhea)

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What are some causes of severe diarrhea?What are some causes of severe diarrhea?– Salmonella, Shigella, Clostridium difficile, Giardia Salmonella, Shigella, Clostridium difficile, Giardia

lamblia, cyclospora, Entamoeba histolyticalamblia, cyclospora, Entamoeba histolytica

What causes gastrointestinal abscesses?What causes gastrointestinal abscesses?– Enterbacteriaceae (mainly E. Coli), S. Faecalis, Enterbacteriaceae (mainly E. Coli), S. Faecalis,

Bacteroides fragilisBacteroides fragilisAll normal flora?All normal flora?

Rank the Gi antibiotic drugs in order of most Rank the Gi antibiotic drugs in order of most used to least used (8).used to least used (8).– Fluoroquinolones, sulfamethoxazole Fluoroquinolones, sulfamethoxazole

trimethoprim, nitroimidazoles, vancomycin, trimethoprim, nitroimidazoles, vancomycin, penicillins, monobactams, cephalosporins penicillins, monobactams, cephalosporins

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FluoroquinolonesFluoroquinolonesWhat is the mechanism of fluoroquinolones?What is the mechanism of fluoroquinolones?– Inhibition of DNA gyrase (Topo 2) and Topo 4. Addition of a flourine Inhibition of DNA gyrase (Topo 2) and Topo 4. Addition of a flourine

expands range of action.expands range of action.– Bind Topo 2 with high affinity. Topo 2 is required for DNA synthesis Bind Topo 2 with high affinity. Topo 2 is required for DNA synthesis

and transcription for unwinding.and transcription for unwinding.– Topo 4 is also inhibited. Topo 4 breaks the chains that are created Topo 4 is also inhibited. Topo 4 breaks the chains that are created

when bacterial chromosomes replicate (Decatenation). Inhibiting when bacterial chromosomes replicate (Decatenation). Inhibiting Topo 4 inhibits DNA synthesis.Topo 4 inhibits DNA synthesis.

How selective are fluoroquinolones?How selective are fluoroquinolones?– They have a much higher affinity for bacterial Topos than human They have a much higher affinity for bacterial Topos than human

Topos. However, they still have side effects that are unrelated to Topos. However, they still have side effects that are unrelated to topoisomerase inhibition.topoisomerase inhibition.

What are the mechanisms of resistance(2)?What are the mechanisms of resistance(2)?– Random point mutations in topoisomerases that produce an enzyme Random point mutations in topoisomerases that produce an enzyme

with a lower affinity for the drugwith a lower affinity for the drug– Drug efflux pumps that pump the drug back out.Drug efflux pumps that pump the drug back out.– Plasmid mediated resistance is “unlikely.” These compounds are Plasmid mediated resistance is “unlikely.” These compounds are

synthetic and do not have analogues in nature.synthetic and do not have analogues in nature.

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Fluoroquinolones continuedFluoroquinolones continuedWhat is the spectrum of activity of flouoroquinolones?What is the spectrum of activity of flouoroquinolones?– Have a wide spectrum, but they generaly have poor actiivity against Have a wide spectrum, but they generaly have poor actiivity against

anaerobes like: bacteroides fragilis, propionibacterium acnes, anaerobes like: bacteroides fragilis, propionibacterium acnes, peptococcus, peptostreptococcus, peptococcus, peptostreptococcus,

What is the main absorption problem with fluoroquinolones?What is the main absorption problem with fluoroquinolones?– CaCa++++ or Mg or Mg++++ may decrease absorption through chelation may decrease absorption through chelation

For which pathogens are fluoroquinolones the DOC?For which pathogens are fluoroquinolones the DOC?– Enterotoxigenic E. coli, Shigella, salmonella, vibrio, Campylobacter Enterotoxigenic E. coli, Shigella, salmonella, vibrio, Campylobacter

jejunijejuni

What are the adverse effects of fluoroquinolones?What are the adverse effects of fluoroquinolones?– Generally better tolerated than bactrimGenerally better tolerated than bactrim– CNS stimulation (GABA inhibition), photosensitivity, GI discomfort CNS stimulation (GABA inhibition), photosensitivity, GI discomfort

with N/Vwith N/V– Accumulate in connective tissues (those high in Ca) and produce Accumulate in connective tissues (those high in Ca) and produce

arthropathy and arthralgia, risk of tendon rupture in children.arthropathy and arthralgia, risk of tendon rupture in children.– Hematological toxicity has kept many off the market.Hematological toxicity has kept many off the market.– Prolonged QT interval with torsades des pointesProlonged QT interval with torsades des pointes

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Fluoroquinolone groupsFluoroquinolone groupsWith what do fluoroquinolones interact?With what do fluoroquinolones interact?– Antacids, dairy products, multivitaminsAntacids, dairy products, multivitamins– Inhibition of CYP 1A2 (theophyllines and cipro)Inhibition of CYP 1A2 (theophyllines and cipro)

Combined with inherent stimulant effects can cause marked CNS Combined with inherent stimulant effects can cause marked CNS stimulationstimulation

How often do we use Group 1 Fluoroquinolones?How often do we use Group 1 Fluoroquinolones?– Almost never, norfloxacin for urinary problemsAlmost never, norfloxacin for urinary problems

Which group do we use for GI? Name some (3).Which group do we use for GI? Name some (3).– Group 2s, which are good for enterobacteriaceae, Group 2s, which are good for enterobacteriaceae, – Ciprofloxacin, ofloxacin, lomefloxacinCiprofloxacin, ofloxacin, lomefloxacin

More likely to inhibit GABA and CYP 1A2More likely to inhibit GABA and CYP 1A2

For what are Group 3 good? Name some (3).For what are Group 3 good? Name some (3).– They have much better (ideal even) pharmacokinetics and they They have much better (ideal even) pharmacokinetics and they

inhibit P450 and GABA much less. They are potent against a wide inhibit P450 and GABA much less. They are potent against a wide variety of organisms. Their spectrum includes all of the second variety of organisms. Their spectrum includes all of the second generation’s bugs plus more. generation’s bugs plus more.

– Levofloxacin, Moxifloxacin, gemifloxacinLevofloxacin, Moxifloxacin, gemifloxacin

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BactrimBactrimWhy do sulfonamides and trimethoprim work well together? Why do sulfonamides and trimethoprim work well together? Why is this combination selective for bacteria over humans?Why is this combination selective for bacteria over humans?– Its synergistic, sulfonamides inhibit the formation of dihydropteroic Its synergistic, sulfonamides inhibit the formation of dihydropteroic

acid while trimethoprim inhibits dihydrofolate reductase. (2 steps in acid while trimethoprim inhibits dihydrofolate reductase. (2 steps in the same pathway)the same pathway)

– Bacterial cells synthesize their own folic acid, whereas humans Bacterial cells synthesize their own folic acid, whereas humans recycle folic acid.recycle folic acid.

What is the spectrum of Sulfamethoxazole-Trimethoprim?What is the spectrum of Sulfamethoxazole-Trimethoprim?– Strep, staph, Neisseria, Moraxella, most Strep, staph, Neisseria, Moraxella, most enterobacteriaceaseenterobacteriacease

(including (including yersiniayersinia), H. Influenza, Legionella, ), H. Influenza, Legionella, Listeria Listeria monocytogenesmonocytogenes, pneumocystis, pneumocystis

– E. coli?E. coli?

What is a nonpharmacologic reason to use What is a nonpharmacologic reason to use sulfamethoxazole-trimethoprim?sulfamethoxazole-trimethoprim?– PharmacoeconomicsPharmacoeconomics

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Sulfamethoxazole-Trimethoprim Sulfamethoxazole-Trimethoprim adverse effectsadverse effects

What adverse effects are common with What adverse effects are common with Sulfamethoxazole-Trimethoprim?Sulfamethoxazole-Trimethoprim?– Similar to slufonamides alone, adverse effects are 75% Similar to slufonamides alone, adverse effects are 75%

dermatological (rash!)dermatological (rash!)– Crystalization in the urine is another problem because Crystalization in the urine is another problem because

the pKa are often above 7the pKa are often above 7Sulfisoxazole is more water soluble, but its half life is not as good Sulfisoxazole is more water soluble, but its half life is not as good as sulfamethoxazole.as sulfamethoxazole.

So we use sulfamethoxazole with trimethoprim for half life So we use sulfamethoxazole with trimethoprim for half life purposespurposes

– Hematologic: rare agranulocytosis and hemolytic anemia Hematologic: rare agranulocytosis and hemolytic anemia – Most are highly protein bound (drug interactions)Most are highly protein bound (drug interactions)

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MetronidzoleMetronidzoleWhen is metronidazole used?When is metronidazole used?– Good for anaerobic coverage. Often used with Good for anaerobic coverage. Often used with

diverticulitis.diverticulitis.

What is the mechanism of metronidazole?What is the mechanism of metronidazole?– The nitro group accepts electrons (from electron-The nitro group accepts electrons (from electron-

transport), a reactive intermediate is formed, DNA and transport), a reactive intermediate is formed, DNA and phospholipid are damaged.phospholipid are damaged.

– BactericidalBactericidal

Why is it selective?Why is it selective?– Mammalian cells utilize oxygen as the final electron Mammalian cells utilize oxygen as the final electron

acceptor in electron transport. acceptor in electron transport. Cancer cells are more anaerobic (and thus more suceptible), but Cancer cells are more anaerobic (and thus more suceptible), but you can’t use it as an anti-cancer drug because the dosage (and you can’t use it as an anti-cancer drug because the dosage (and toxicity) is too high.toxicity) is too high.

What is the spectrum of metronidazole?What is the spectrum of metronidazole?– Bacteroides fragilis, clostridium, helicobacterBacteroides fragilis, clostridium, helicobacter

Page 45: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

MetronidazoleMetronidazole

What are the adverse effects of metronidazole?What are the adverse effects of metronidazole?– Most common are n/v, headache, dry mouth, metallic Most common are n/v, headache, dry mouth, metallic

tastetaste– Disulfiram like reactionDisulfiram like reaction

He harped on this (or maybe it was someone else, but someone He harped on this (or maybe it was someone else, but someone harped on it), make damn sure you warn your patients about harped on it), make damn sure you warn your patients about disulfiram-like reactions. All humans are alcoholics.disulfiram-like reactions. All humans are alcoholics.

– Rare CNS disturbancesRare CNS disturbances– It is a possible mutagenIt is a possible mutagen

What is different about Tinidazole?What is different about Tinidazole?– Consider it the same (as metronidazole) for this courseConsider it the same (as metronidazole) for this course

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VancomycinVancomycin

What class is Vancomycin?What class is Vancomycin?– Vancomycin is a glycopeptideVancomycin is a glycopeptide

NOTNOT an aminoglycoside. an aminoglycoside.

What is its mechanism? For what GI bug might you What is its mechanism? For what GI bug might you use Vancomycin?use Vancomycin?– Binds with high affinity to the d-alanyl-d-alanine terminus Binds with high affinity to the d-alanyl-d-alanine terminus

of the peptidoglycan precursors and inhibit cross-linking.of the peptidoglycan precursors and inhibit cross-linking.Thus, a cell wall inhibitorThus, a cell wall inhibitor

– It has great activity against Clostridium difficile.It has great activity against Clostridium difficile.

What percentage of vancomycin is absorbed What percentage of vancomycin is absorbed orally?orally?– None, but we can give it orally and get minimal adverse None, but we can give it orally and get minimal adverse

effects. It still treats clostridium difficile (orally).effects. It still treats clostridium difficile (orally).

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ToxicologyToxicology

Page 48: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

I don’t know a title for this slideI don’t know a title for this slideWhat is the best database for determining the acting agent during a What is the best database for determining the acting agent during a poisoning?poisoning?– Your friendly local poison centerYour friendly local poison center

1-800-3poison1-800-3poison

What are the initial considerations you should always include when What are the initial considerations you should always include when dealing with an emergently poisoned person?dealing with an emergently poisoned person?– Ensure airway, cervical spine protection, ventilation, and circulation.Ensure airway, cervical spine protection, ventilation, and circulation.

What do you do for a person with acute mental status changes in the What do you do for a person with acute mental status changes in the ER?ER?– If you can’t disprove hypoglycemia, give some glucose. Give oxygen. If If you can’t disprove hypoglycemia, give some glucose. Give oxygen. If

alcoholic, add thiamine.alcoholic, add thiamine.– Think about opioids (as the inciting agent) if they have depressed CNS. Think about opioids (as the inciting agent) if they have depressed CNS.

Naloxone can precipitate abrupt withdrawal, so don’t give it unless you have Naloxone can precipitate abrupt withdrawal, so don’t give it unless you have to. Just handle the airway if possible. to. Just handle the airway if possible.

– Handle the ABCs. (airwaybreathingcirculation)Handle the ABCs. (airwaybreathingcirculation)What two drugs do you never give to an unconcious person?What two drugs do you never give to an unconcious person?– Physostagmine and flumazanil (benzo antagonist), the latter because of Physostagmine and flumazanil (benzo antagonist), the latter because of

withdrawal and seizure precipitation.withdrawal and seizure precipitation.

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Toxic SyndromesToxic Syndromes

What are toxic syndromes?What are toxic syndromes?– These are “poisoning patterns” that are useful if you can These are “poisoning patterns” that are useful if you can

spot them.spot them.

Describe anticholinesterase/cholinergic syndrome?Describe anticholinesterase/cholinergic syndrome?– Stimulating the parasympathetic and sympathetic Stimulating the parasympathetic and sympathetic

nervous system at the same time causes:nervous system at the same time causes:SLUDGE + unconcious, normal BPSLUDGE + unconcious, normal BP

– ((SSalivation, alivation, LLacrimation, acrimation, UUrination, rination, DDefecation, efecation, GGastrointestinal astrointestinal cramping, cramping, EEmesis) mesis)

Also sweating, miosis, wheezing, bradycardia, general Also sweating, miosis, wheezing, bradycardia, general parasympathetic excess signsparasympathetic excess signs

Now I guess I’m gonna writeup the other Now I guess I’m gonna writeup the other syndromes. They’re kind of cool I guess and good syndromes. They’re kind of cool I guess and good to know for life and medical practice. Go over it or to know for life and medical practice. Go over it or skip it, I don’t care.skip it, I don’t care.

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SyndromesSyndromes

Describe extrapyramidal syndrome. What causes it?Describe extrapyramidal syndrome. What causes it?– Movement disorders, rigidity, tremor, torticolis, opisthotonus, etc.Movement disorders, rigidity, tremor, torticolis, opisthotonus, etc.– Caused by dopamine antagonists (butyrophenones and phenothiazines) and Caused by dopamine antagonists (butyrophenones and phenothiazines) and

mimicked by strychnine and tetanusmimicked by strychnine and tetanusDescribe anticholinergic syndrome. What causes it?Describe anticholinergic syndrome. What causes it?– Mydriasis, dry (mouth), dysphagia, blurred near vision, tachycardia, Mydriasis, dry (mouth), dysphagia, blurred near vision, tachycardia,

hypertensionhypertension– Caused by atropine, scopolamine, tricyclic antidepressants in overdose, Caused by atropine, scopolamine, tricyclic antidepressants in overdose,

jimson wed and some mushroomsjimson wed and some mushroomsDescribe hemoglobinopathy syndrome. What causes it?Describe hemoglobinopathy syndrome. What causes it?– Hypoxia, headache, disorientation, coma, n/v, cardiac dysfunction, acidosis Hypoxia, headache, disorientation, coma, n/v, cardiac dysfunction, acidosis

and deathand death– Carbon monoxide toxicity or methemoglobinemiaCarbon monoxide toxicity or methemoglobinemia

Describe metal fume fever (this is really interesting). What causes it?Describe metal fume fever (this is really interesting). What causes it?– Influenza-like: chills, n/v, myalgia, fever, leukocytosis, cough, respiratory Influenza-like: chills, n/v, myalgia, fever, leukocytosis, cough, respiratory

distress.distress.– Happens in foundry workers, welders, etc. who inhale fumes.Happens in foundry workers, welders, etc. who inhale fumes.

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More syndromesMore syndromesOpioid syndrome.Opioid syndrome.– Pinpoint pupils, respiratory depression and hypotension.Pinpoint pupils, respiratory depression and hypotension.

You can use naloxone, but be careful because withdrawals are tough and they You can use naloxone, but be careful because withdrawals are tough and they make the patient hard to deal withmake the patient hard to deal with

– Believe it or not, this syndrome is caused by opioidsBelieve it or not, this syndrome is caused by opioidsSympathomimetic excess syndrome.Sympathomimetic excess syndrome.– Nervousness, tremor, Nervousness, tremor, diaphoresisdiaphoresis, CNS excitation, hypertension, , CNS excitation, hypertension,

tachycardia, and seizurestachycardia, and seizuresDiaphoresis, prescence of bowol sounds, and lack of urinary retention together Diaphoresis, prescence of bowol sounds, and lack of urinary retention together are pretty specific and help you rule out anticholinergic poisoning or hypoglycemiaare pretty specific and help you rule out anticholinergic poisoning or hypoglycemia

– Cause not listed (my guess is epi or cocaine)Cause not listed (my guess is epi or cocaine)Withdrawal syndrome.Withdrawal syndrome.– Anxiety and drug seeking behavior. Opioid withdrawal has mydriasis, Anxiety and drug seeking behavior. Opioid withdrawal has mydriasis,

piloerection,rhinorrhea, and lacrimation. Non-opioid depressants have more piloerection,rhinorrhea, and lacrimation. Non-opioid depressants have more severe withdrawal (as you know) and can have seizure, hallucinations, and severe withdrawal (as you know) and can have seizure, hallucinations, and hyperpyrexia.hyperpyrexia.

– Obvious cause.Obvious cause.Serotonin Syndrome.Serotonin Syndrome.– Hyperreflexia, spasticity, hypertension, hyperthermia, altered mental statusHyperreflexia, spasticity, hypertension, hyperthermia, altered mental status– Many things can cause excess serotoninMany things can cause excess serotonin

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What causes what?What causes what?What does a wide QRS indicate (that the patient has toxicly ingested)?What does a wide QRS indicate (that the patient has toxicly ingested)?– Any sodium channel blockerAny sodium channel blocker

What causes sinus tachycardia?What causes sinus tachycardia?– A million things: fear, anger, excitement, stimulants, hallucinogens, A million things: fear, anger, excitement, stimulants, hallucinogens,

hypoglycemic, pain.hypoglycemic, pain.

What causes sinus bradycardia?What causes sinus bradycardia?– Beta blocker, calcium channel blocker, cholinergics, and digitalis.Beta blocker, calcium channel blocker, cholinergics, and digitalis.

What causes metabolic acidosis?What causes metabolic acidosis?– Aspirin, methanol, ethylene glycolAspirin, methanol, ethylene glycol

What causes GI dysfunction?What causes GI dysfunction?– Non-specific, (anything)Non-specific, (anything)

What does he do when he sees someone with altered mental status? What does he do when he sees someone with altered mental status? What can cause altered mental status?What can cause altered mental status?– Use a benzodiazepine, probably lorazepam or diazepam.Use a benzodiazepine, probably lorazepam or diazepam.– Infection, tumors, metabolic problems (thyroid, calcium, CO2, sugar), Infection, tumors, metabolic problems (thyroid, calcium, CO2, sugar),

withdrawal, poison, heat/cold, primary psychiatric problemwithdrawal, poison, heat/cold, primary psychiatric problem

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More information without a unifying pattern or More information without a unifying pattern or theme of any kindtheme of any kind

What drug class should be used for seizures? What causes toxicologic What drug class should be used for seizures? What causes toxicologic seizures?seizures?– BenzodiazepinesBenzodiazepines– Global cortical dysfunction, which is why phenytoin is not useful.Global cortical dysfunction, which is why phenytoin is not useful.

What tests should be run in all non-trivial toxicology cases?What tests should be run in all non-trivial toxicology cases?– Electrolytes, BUN, creatinine, glucose, arterial blood gases, liver function Electrolytes, BUN, creatinine, glucose, arterial blood gases, liver function

tests, EKG, and occasionally x-rays. (and get extra blood for later testing)tests, EKG, and occasionally x-rays. (and get extra blood for later testing)What are urine tox screens good for? For what drugs are a serum What are urine tox screens good for? For what drugs are a serum levels useful?levels useful?– They are useful to They are useful to confirmconfirm an existing suspicion an existing suspicion– Lithium, dig, aspirin, methanol, ethylene glycol, theophylline, salicylate, Lithium, dig, aspirin, methanol, ethylene glycol, theophylline, salicylate,

acetominophenacetominophenFor what are x-rays good in a toxified patient?For what are x-rays good in a toxified patient?– Tell you about heart size, lung infiltrate, condoms full of cocaine.Tell you about heart size, lung infiltrate, condoms full of cocaine.

Is it a good idea to run a gastric decontamination? Is it a good idea to run a gastric decontamination? – This is an incredibly contentious idea with minimal consensusThis is an incredibly contentious idea with minimal consensus– It is a bad idea to It is a bad idea to reflexivelyreflexively do any of these (to do them without thinking on do any of these (to do them without thinking on

any patient): charcoal, lavage, ipicap, flushing. any patient): charcoal, lavage, ipicap, flushing.

Page 54: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

Gastric decontaminationGastric decontaminationName two decontamination procedures that are pretty well Name two decontamination procedures that are pretty well universally accepted and a good idea.universally accepted and a good idea.– Copious irrigation for something in the eye, soap and water for skin Copious irrigation for something in the eye, soap and water for skin

contamination.contamination.

How awesome is Syrup of Ipicac?How awesome is Syrup of Ipicac?– No utility in the ER, can be really bad if you have ingested something No utility in the ER, can be really bad if you have ingested something

sharpsharp– Was one of the most ridiculous Was one of the most ridiculous Family Guy scenesFamily Guy scenes ever, however. ever, however.

How awesome is the olde stomach pump (gastric lavage)?How awesome is the olde stomach pump (gastric lavage)?– Very rarely useful. Only if you have a big reason to believe there is Very rarely useful. Only if you have a big reason to believe there is

a bunch of stuff still in the stomach.a bunch of stuff still in the stomach.

How about some charcoal?How about some charcoal?– More useful, but still dangerous and only useful when recent (2 hour) More useful, but still dangerous and only useful when recent (2 hour)

ingestion.ingestion.

What about flushing out the GI tract?What about flushing out the GI tract?– This works by having the person drink the hell out of some MiraLax This works by having the person drink the hell out of some MiraLax

(osmotic diarrheal agent). They hate you and the nurses hate you. (osmotic diarrheal agent). They hate you and the nurses hate you.

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Specific CurativesSpecific Curatives

What would you give if you ever saw someone with What would you give if you ever saw someone with iodine poisoning?iodine poisoning?– StarchStarch

How does one acquire hydroflouric acid poisoning? How does one acquire hydroflouric acid poisoning? How does this poisoning work? How is it treated?How does this poisoning work? How is it treated?– Don’t use gloves when cleaning copper?Don’t use gloves when cleaning copper?– Flouride complexes the calcium, causes neural irritability Flouride complexes the calcium, causes neural irritability

in the fingertips. Causes intense pain.in the fingertips. Causes intense pain.– Give calcium gluconate topically, locally (arterially)Give calcium gluconate topically, locally (arterially)

When should you use dilution (give fluids orally)?When should you use dilution (give fluids orally)?– Probably never, it often makes things worse.Probably never, it often makes things worse.

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Antidotes!Antidotes!Give the antidote for each toxicant.Give the antidote for each toxicant.

IronIron– DeferoxamineDeferoxamine

OrganophosphatesOrganophosphates– 2-pam chloride and atropine2-pam chloride and atropine

CyanideCyanide– Amyl nitrite, sodium nitrite, and thiosulfateAmyl nitrite, sodium nitrite, and thiosulfate– Or hydroxycobalaminOr hydroxycobalamin

OpiatesOpiates– Naloxone or naltrexoneNaloxone or naltrexone

CarbamatesCarbamates– AtropineAtropine

Methanol or Ethylene glycolMethanol or Ethylene glycol– Ethanol or 4-methyl pyrazoleEthanol or 4-methyl pyrazole

Carbon monoxideCarbon monoxide– Oxygen, hyperbaric oxygenOxygen, hyperbaric oxygen

Tricyclic antidepressantsTricyclic antidepressants– Sodium bicarbonateSodium bicarbonate

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Elimination MechanismsElimination Mechanisms

What are some ways to get rid of a pre-absorbed What are some ways to get rid of a pre-absorbed toxicant?toxicant?– Ion trapping in urineIon trapping in urine– Charcoal administrationCharcoal administration

Sucks toxicant out of the bowelSucks toxicant out of the bowel

– HemodialysisHemodialysisLow molecular weight, non-protein bound, water soluble Low molecular weight, non-protein bound, water soluble toxicantstoxicants

– Plasmapheresis and exchange perfusionPlasmapheresis and exchange perfusion

When would you consider these?When would you consider these?– When it can be removed and the patient is deteriorating When it can be removed and the patient is deteriorating

or not responding to supportive care, or if you or not responding to supportive care, or if you knowknow it’s it’s going to get bad later.going to get bad later.

– Or if you have impairment of the normal excretory route Or if you have impairment of the normal excretory route (like kidney failure)(like kidney failure)

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Snake BitesSnake Bites

Page 59: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

Snakes on a PlaneSnakes on a Plane

30 species of poisonous snakes in the U.S.30 species of poisonous snakes in the U.S.Most bites in the U.S. are ___.Most bites in the U.S. are ___.– Pit viper bites. (copper head cotton mouth, rattlesnakes. Pit viper bites. (copper head cotton mouth, rattlesnakes.

They all have a pit that is sensitive to heat)They all have a pit that is sensitive to heat)

Most bites in Arkansas are ____.Most bites in Arkansas are ____.– Copperhead bites, which are not as bad as cottenmouth, Copperhead bites, which are not as bad as cottenmouth,

which are not as bad as rattlesnakes.which are not as bad as rattlesnakes.

Describe Pit VipersDescribe Pit Vipers– Depressed (pit) areas behind their paired nostrils act as Depressed (pit) areas behind their paired nostrils act as

heat sensing organs. They have triangular heads, heat sensing organs. They have triangular heads, elliptical pupils, and paired yellow hypodermic fangs.elliptical pupils, and paired yellow hypodermic fangs.

– Copperheads have red heads, cottonmouths have white Copperheads have red heads, cottonmouths have white oral mucosa, and rattlesnakes have rattlesoral mucosa, and rattlesnakes have rattles

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BehaviorBehavior

Describe the behavior of:Describe the behavior of:– RattlesnakesRattlesnakes

Smart, don’t want to bother you. They will give you an Smart, don’t want to bother you. They will give you an opportunity to not get bitten.opportunity to not get bitten.

– CottonmouthsCottonmouthsAggressive, obnoxious creaturesAggressive, obnoxious creatures

– Copper headCopper headAn indolent, lazy creature. Won’t do anything.An indolent, lazy creature. Won’t do anything.

Describe Coral snakes (rare bites in AR).Describe Coral snakes (rare bites in AR).– 12-18 inches long, red, yellow, and black bands. Red to 12-18 inches long, red, yellow, and black bands. Red to

yellow, round black head, round pupils. No fangs, they yellow, round black head, round pupils. No fangs, they bite and chew on you.bite and chew on you.

Not to be confused with king snakes, red on black, red snoutNot to be confused with king snakes, red on black, red snout

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VenomVenomFeatures of venemous snake bitesFeatures of venemous snake bites– Bigger snakes have more venom, number of bites, how deep the Bigger snakes have more venom, number of bites, how deep the

bite is, location of the bite.bite is, location of the bite.– Pit vipers leave puncture wounds. Usually two, but can be one or Pit vipers leave puncture wounds. Usually two, but can be one or

ten. Some bites are dry (20-30%). Some punctures are not snake ten. Some bites are dry (20-30%). Some punctures are not snake bites.bites.

– Coral snakes (and some others) just leave scratchesCoral snakes (and some others) just leave scratches

Compare the severity of each snakes venom.Compare the severity of each snakes venom.– Rattlesnake > cottonmouth > copperhead. Coral snakes are Rattlesnake > cottonmouth > copperhead. Coral snakes are

different (curare-esque), but very toxic.different (curare-esque), but very toxic.

VenomsVenoms– Once injected, they bind to tissue and also circulate. Only the Once injected, they bind to tissue and also circulate. Only the

circulating venom can be neutralized. Arkansas pit vipers are circulating venom can be neutralized. Arkansas pit vipers are neurotoxic, but not significantly.neurotoxic, but not significantly.

– Usually get a lot of swelling.Usually get a lot of swelling.– Rhabdomyalisis is a common problem and can cause renal failure Rhabdomyalisis is a common problem and can cause renal failure

through myoglobin release.through myoglobin release.

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Snake SymptomsSnake SymptomsWhat are the symptoms/signs present after pit viper bites (crotaline What are the symptoms/signs present after pit viper bites (crotaline venom)? What lab values?venom)? What lab values?– Immediate pain, hemorrhagic blebs, and swelling occur. Swelling continues Immediate pain, hemorrhagic blebs, and swelling occur. Swelling continues

to worsen while myonecrosis and rhabdomyalisis occur.to worsen while myonecrosis and rhabdomyalisis occur.Symptoms can take hours to developSymptoms can take hours to develop

– Systemic symptoms may include weakness, nausea, restlessness, paralysis, Systemic symptoms may include weakness, nausea, restlessness, paralysis, and renal failure.and renal failure.

– INR, PT, PTT all go up. DIC can occur. INR, PT, PTT all go up. DIC can occur. Can allergic reaction to a snake bite occur?Can allergic reaction to a snake bite occur?– YesYes

How do you grade pit viper invenomation?How do you grade pit viper invenomation?– Dry bite, grade 0Dry bite, grade 0

2 puncture wounds, little pain, no swelling, watched for 8-10 hours2 puncture wounds, little pain, no swelling, watched for 8-10 hours– Mild invenomationMild invenomation

Puncture wounds, some swelling, no systemic symptomsPuncture wounds, some swelling, no systemic symptoms– Moderate InvenomationModerate Invenomation

Local wound, hemorrhages, bullae, dramatic swelling extending well beyond site Local wound, hemorrhages, bullae, dramatic swelling extending well beyond site of bite. Systemic signs: anxious, pain, altered mental status. Abnormal lab of bite. Systemic signs: anxious, pain, altered mental status. Abnormal lab findings. Urine myoglobin. Stable vital signsfindings. Urine myoglobin. Stable vital signs

– Severe invenomationSevere invenomationLocal wound with dramatic swelling, as above but cardiovascular instabilityLocal wound with dramatic swelling, as above but cardiovascular instability

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Coral VenomCoral Venom

Describe coral snake invenomation.Describe coral snake invenomation.– Usually on the hand, you have to try to get bitten. Usually on the hand, you have to try to get bitten.

They bite and chew, salivate the venom. They bite and chew, salivate the venom.– Significant delay until onset of symptoms, 40% Significant delay until onset of symptoms, 40%

dry bites. 12 or more hours may pass before dry bites. 12 or more hours may pass before symptoms occur.symptoms occur.

– Competitive neuromuscular blocker. Paralysis, Competitive neuromuscular blocker. Paralysis, HypoventilationHypoventilationrespiratory acidosis occur.respiratory acidosis occur.

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Cox vs. TurkCox vs. Turk

When is surgery a possible application?When is surgery a possible application?– Usually when bite is on a digit, face, tongue, or neck. Usually when bite is on a digit, face, tongue, or neck.

Otherwise snakebite is a medical illness with surgical Otherwise snakebite is a medical illness with surgical complications.complications.

– The surgery/medicine rivalry can be ridiculous. If you The surgery/medicine rivalry can be ridiculous. If you treat early enough, surgery is usually unnecessary. treat early enough, surgery is usually unnecessary. However, there are three cases where surgery is useful:However, there are three cases where surgery is useful:

Badly invenomated digitBadly invenomated digitIf a compartment syndrome is developing:If a compartment syndrome is developing:

– Rising pressure from swelling blocks off the blood supply. You need Rising pressure from swelling blocks off the blood supply. You need to make sure that the pressure is actually high and blocking blood to make sure that the pressure is actually high and blocking blood flow, because sometimes huge swelling can have low pressure and flow, because sometimes huge swelling can have low pressure and thus be non-surgical. If compartment syndrome does occur, thus be non-surgical. If compartment syndrome does occur, surgeons can cut the fascia and restore blood flow.surgeons can cut the fascia and restore blood flow.

Necrotic tissue may need to be debrided, reconstructive surgery Necrotic tissue may need to be debrided, reconstructive surgery may also be necessarymay also be necessary

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HospitalizationHospitalization

When should you admit patients to the hospital?When should you admit patients to the hospital?– With a viper bite, hospitalize overnight regardless of With a viper bite, hospitalize overnight regardless of

symtpoms.symtpoms.

What should you do outside the hospital?What should you do outside the hospital?– Immobilize the bite site and get their ass to the Immobilize the bite site and get their ass to the

hospital. Don’t use a tourniquet, unless it just blocks hospital. Don’t use a tourniquet, unless it just blocks lymphatics (especially not for pit vipers because it will lymphatics (especially not for pit vipers because it will keep the venom localized and make them lose the keep the venom localized and make them lose the extremity). Don’t use ice. Go to the hospital.extremity). Don’t use ice. Go to the hospital.

If you’re out in the middle of nowhere, call in a helicopter. If you’re out in the middle of nowhere, call in a helicopter. Helicopter rides are fun. And if I died of a snake bite, I would Helicopter rides are fun. And if I died of a snake bite, I would want it to be in a helicopter.want it to be in a helicopter.

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Treatment optionsTreatment optionsWhen should you start adding coagulation factors and platelets?When should you start adding coagulation factors and platelets?– After administering anti venom (otherwise venom will just eat the new After administering anti venom (otherwise venom will just eat the new

coagulation stuff)coagulation stuff)Who needs antivenom?Who needs antivenom?– Must have some systemic symptoms or severe local effects, swelling at the Must have some systemic symptoms or severe local effects, swelling at the

site.site.– If you aren’t sure, call the poison center. If you aren’t sure, call the poison center.

What antivenom does one use for pit viper bites? How do you What antivenom does one use for pit viper bites? How do you administer it?administer it?– CroFab, a polyvalent antivenom derived from sheepCroFab, a polyvalent antivenom derived from sheep– Keep giving vials until their coagulation stabilizes, then two vials every six Keep giving vials until their coagulation stabilizes, then two vials every six

hours for three dosings (24 hour total dosing).hours for three dosings (24 hour total dosing).What do you do if they might have been bitten by a coral snake?What do you do if they might have been bitten by a coral snake?– Play no games.Play no games.– Give antivenom, put them in the ICU, keep them there for at least day or Give antivenom, put them in the ICU, keep them there for at least day or

two. two. Antivenom is a highly antigenic horse serum, so watch out.Antivenom is a highly antigenic horse serum, so watch out.

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Antihelmintic DrugsAntihelmintic Drugs

Page 68: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

Worm typesWorm types

What is the most common cestode?What is the most common cestode?– Taenia saginata (beef tapeworm) is the most Taenia saginata (beef tapeworm) is the most

common tapeworm.common tapeworm.

What is the most common nematode?What is the most common nematode?– Ascaris lumbricoides is the most common Ascaris lumbricoides is the most common

roundworm.roundworm.

What is the most common trematode?What is the most common trematode?– Schistosoma mansoni (blood fluke) is the Schistosoma mansoni (blood fluke) is the

most common fluke.most common fluke.

Page 69: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

Jump right inJump right in

Severity of helminthic infection is determined by what?Severity of helminthic infection is determined by what?– Extent of initial exposureExtent of initial exposure

For what is Niclosamide (niclocide) used?For what is Niclosamide (niclocide) used?– Drug of choice for most cestode infectionsDrug of choice for most cestode infections

ON TEST ON TEST

What is niclocide’s mechanism? How well does it kill adults? Ova?What is niclocide’s mechanism? How well does it kill adults? Ova?– Inhibition of glucose uptake and energy production from anaerobic Inhibition of glucose uptake and energy production from anaerobic

metabolism in the parasite, resulting in detachment from the intestinal wall metabolism in the parasite, resulting in detachment from the intestinal wall and evacuation by normal peristalsisand evacuation by normal peristalsis

– Lethal effect kills adults but not ovaLethal effect kills adults but not ovaSo consider purging the GI tract after treatment to prevent migration So consider purging the GI tract after treatment to prevent migration (cysicercosis)(cysicercosis)

– House pilot episode: neurocysticercosisHouse pilot episode: neurocysticercosis

What is cysticercosis?What is cysticercosis?– Larvae invade intestinal wall and lodge in other tissues (like the brain)Larvae invade intestinal wall and lodge in other tissues (like the brain)

How is it administered? What side effects are common?How is it administered? What side effects are common?– Taken orallyTaken orally– Adverse effects are few, abdominal discomfort happens.Adverse effects are few, abdominal discomfort happens.

Page 70: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

PraziquantilPraziquantil

What is Praziquantil used for?What is Praziquantil used for?– It is often considered the drug of choice for all cestode It is often considered the drug of choice for all cestode

and trematode infections and trematode infections

What is the mechanism of Praziquantil?What is the mechanism of Praziquantil?– Increases permeability of worm cell membrane to CaIncreases permeability of worm cell membrane to Ca++++

ions. Influx of calcium produces a massive contracture ions. Influx of calcium produces a massive contracture and impairs their ability to attach to the intestinal wall.and impairs their ability to attach to the intestinal wall.

– Slightly higher doses also produce tegumental damage to Slightly higher doses also produce tegumental damage to the worm which activates host defenses.the worm which activates host defenses.

Describe the pharmacokinetics of praziquantil.Describe the pharmacokinetics of praziquantil.– Taken orally, absorbed well, extensive first pass Taken orally, absorbed well, extensive first pass

metabolismmetabolism

What adverse effects are common?What adverse effects are common?– abdominal discomfort, fever, sedation, headacheabdominal discomfort, fever, sedation, headache

Page 71: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

BenzimidazolesBenzimidazolesFor what are benzimidazoles used?For what are benzimidazoles used?– Drugs of choice for most infections produced by nematodesDrugs of choice for most infections produced by nematodes– They are broad spectrum, though specific drugs may be preferable They are broad spectrum, though specific drugs may be preferable

for specific organismsfor specific organisms

What is the mechanism of Mebendazole (Vermox)? Is it What is the mechanism of Mebendazole (Vermox)? Is it useful for adults or ova? For what bug is it useful?useful for adults or ova? For what bug is it useful?– Inhbibition of helminth glucose uptake resulting in reduced glycogen Inhbibition of helminth glucose uptake resulting in reduced glycogen

and ATP levels. Also inhibits microtubule polymerization by beta-and ATP levels. Also inhibits microtubule polymerization by beta-tubulintubulin

Helminth selectivity is achieved because of higher affinity for helminth Helminth selectivity is achieved because of higher affinity for helminth targetstargets

– Lethal effect extends to both adults and ova, therefore no need to Lethal effect extends to both adults and ova, therefore no need to purgepurge

– Drug of choice for pinworms (E. vermicularis). Reinfection with Drug of choice for pinworms (E. vermicularis). Reinfection with pinworms is common, so family members should also be treated.pinworms is common, so family members should also be treated.

What is the treatment for pinworms?What is the treatment for pinworms?– Mebendazole and possibly an anti-itch cream.Mebendazole and possibly an anti-itch cream.

Page 72: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

ThiabendazoleThiabendazoleWhat is the mechanism of Thiabendazole?What is the mechanism of Thiabendazole?– Mechanims is similar to but different from mebendazole in that it Mechanims is similar to but different from mebendazole in that it

(also) inhibits fumarate reductase which is essential for anaerobic (also) inhibits fumarate reductase which is essential for anaerobic metabolism of helminthsmetabolism of helminths

What life cycle forms does thiabendazole kill?What life cycle forms does thiabendazole kill?– Kills adult and ova, but larvae from T. spiralis in tissues is not killedKills adult and ova, but larvae from T. spiralis in tissues is not killed

How is thiabendazole absorbed?How is thiabendazole absorbed?– Rapidly absorbed in the GI tractRapidly absorbed in the GI tract

What side effects are common with thiabendazole?What side effects are common with thiabendazole?– Big side effects, usually prevent use for GI infections n/v, diarrhea, Big side effects, usually prevent use for GI infections n/v, diarrhea,

vertigo, crystalluria, leukopenia, stevens-johnson syndromevertigo, crystalluria, leukopenia, stevens-johnson syndrome

For what is thiabendazole used?For what is thiabendazole used?– Generally used topically for cutaneous larva migrans (creeping Generally used topically for cutaneous larva migrans (creeping

eruption) often seen with Strongyloides stercoralis infections.eruption) often seen with Strongyloides stercoralis infections.

Page 73: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

AlbendazoleAlbendazole

What is Albendazole? For what is it used?What is Albendazole? For what is it used?– A newer benzimidazole available for A newer benzimidazole available for

“compassionate use” from smithkline beecham“compassionate use” from smithkline beecham– Drug of choice for neurocysticercosis and Drug of choice for neurocysticercosis and

hydatid diseasehydatid disease

Page 74: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

Pyrantel Pamoate (antiminth)Pyrantel Pamoate (antiminth)For what is pyrantel used?For what is pyrantel used?– Drug of choice for several nematode infections Drug of choice for several nematode infections

(hookworm)(hookworm)

How does pyrantel work?How does pyrantel work?– Depolarizes the myoneural junction of helminth muscle Depolarizes the myoneural junction of helminth muscle

via cholinesterase inhibition to cause spastic paralysisvia cholinesterase inhibition to cause spastic paralysisWorms are passed alive, with little chance of absorption of Worms are passed alive, with little chance of absorption of disintegration productsdisintegration products

– Affinity for mammallian acetylcholinesterase is much less Affinity for mammallian acetylcholinesterase is much less than that for helminthsthan that for helminths

What adverse effects are common?What adverse effects are common?– Adverse effects include GI symptoms, fever, CNS effects Adverse effects include GI symptoms, fever, CNS effects

due to nicotinic actionsdue to nicotinic actions

Contraindications?Contraindications?– Contraindicated in pregnancy, children under one year Contraindicated in pregnancy, children under one year

old, or with piperazineold, or with piperazine

Page 75: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

Less used Anihelmintic drugsLess used Anihelmintic drugs““What you need to know for these is what they are, how they work, what What you need to know for these is what they are, how they work, what they are used for.” But all I’m learning is what he said about them:they are used for.” But all I’m learning is what he said about them:Piperazine (vermazine)Piperazine (vermazine)– Acts as an inhibitory neurotransmitter helminth analogue producing Acts as an inhibitory neurotransmitter helminth analogue producing

hyperpolarization and flacid paralysis\a lumbricoides and e vermiculoarishyperpolarization and flacid paralysis\a lumbricoides and e vermiculoarisIvermectinIvermectin– Drug of choice for nematode O. volvulus (“river blindness”)Drug of choice for nematode O. volvulus (“river blindness”)

DiethylcarbamazineDiethylcarbamazine– Drug of choice for exotic nematode infections, W. bancrofti, B. malavi, and L. Drug of choice for exotic nematode infections, W. bancrofti, B. malavi, and L.

LoaLoa– Often introduced into table salt at 0.4%Often introduced into table salt at 0.4%

Metrifonate (bilarcil)Metrifonate (bilarcil)– Low cost, used for treatment of urinary shistosomiasis in AfricaLow cost, used for treatment of urinary shistosomiasis in Africa– Organophosphorus inhibitor of cholinesteraseOrganophosphorus inhibitor of cholinesterase

OxamiquineOxamiquine– Alternate drug for treatment of trematode S. mansoni infectionsAlternate drug for treatment of trematode S. mansoni infections

BithionolBithionol– Drug of choice for treatment of trematode F. hepaticaDrug of choice for treatment of trematode F. hepatica– Available from the CDC onlyAvailable from the CDC only

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AntiprotozoalsAntiprotozoals

Page 77: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

MalariaMalariaHow many people are “affected” by malaria?How many people are “affected” by malaria?– 2.4 billion (40%) of the population2.4 billion (40%) of the population

Which two species of malaria produce secondary liver forms which cause Which two species of malaria produce secondary liver forms which cause relapses of clinical symptoms (dormant in the liver)?relapses of clinical symptoms (dormant in the liver)?– P. vivax and P. ovaleP. vivax and P. ovale

What are the four categories of chemotherapy for malaria?What are the four categories of chemotherapy for malaria?– Prophylaxis- prevention of a clinical attack by prevention of the erythrocytic Prophylaxis- prevention of a clinical attack by prevention of the erythrocytic

stagestageDOC Mefloquine (in areas with chloroquine resistance)DOC Mefloquine (in areas with chloroquine resistance)Chloroquine can be used if no resistance, doxycycline (2Chloroquine can be used if no resistance, doxycycline (2ndnd choice) and choice) and pyrimethamine plus sulfadoxine (3pyrimethamine plus sulfadoxine (3rdrd choice) are alternatives choice) are alternatives

– Clinical Cure- interrupts erythrocytic stage and terminates attackClinical Cure- interrupts erythrocytic stage and terminates attackDOC is mefloquine (unless chloroquine sensitive)DOC is mefloquine (unless chloroquine sensitive)Secondary choice is Quinine, 3Secondary choice is Quinine, 3rdrd choice is pyrimethamine plus sulfadoxine choice is pyrimethamine plus sulfadoxine

– Radical Cure- eliminates all parasites from bodyRadical Cure- eliminates all parasites from bodyP. vivax and P. ovale: P. vivax and P. ovale:

– Primaquine is the only available compound for exoerythrocytic infection. So we use Primaquine is the only available compound for exoerythrocytic infection. So we use primaquine plus an agent effective against erythrocytic forms (e.g. mefloquine) are used.primaquine plus an agent effective against erythrocytic forms (e.g. mefloquine) are used.

P. falciparum and P. malariae: just use the clinical cure drug and you will completely P. falciparum and P. malariae: just use the clinical cure drug and you will completely eliminate the organism, since they don’t leave residual liver infectioneliminate the organism, since they don’t leave residual liver infection

– Gametocidal therapy- destroys sexual forms in bloodGametocidal therapy- destroys sexual forms in bloodFalciparum: primaquineFalciparum: primaquineVivax and malariae: chloroquineVivax and malariae: chloroquine

Page 78: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

ChloroquineChloroquineFor what is Chloroquine (Aralen) used?For what is Chloroquine (Aralen) used?– Developed by Nazi Germany, it is the drug of choice for suppressive Developed by Nazi Germany, it is the drug of choice for suppressive

treatment and acute uncomplicated attacks, if not resistanttreatment and acute uncomplicated attacks, if not resistant

Why is chloroquine a pretty good antimalarial?Why is chloroquine a pretty good antimalarial?– Effective against erythrocytic forms, is fast acting (1-2) days, most Effective against erythrocytic forms, is fast acting (1-2) days, most

versatile antimalarial drugversatile antimalarial drug

What is chloroquine’s mechanism?What is chloroquine’s mechanism?– Moa: blocks transcription and accumulates with plasmodiumMoa: blocks transcription and accumulates with plasmodium

How is it administered?How is it administered?– Administered orally or parenterally, half life 6-7 days, give slowly or Administered orally or parenterally, half life 6-7 days, give slowly or

in small divided doses i.v. or i.m. to prevent lethal concentrations in small divided doses i.v. or i.m. to prevent lethal concentrations building up in the plasmabuilding up in the plasma

How does resistance occur?How does resistance occur?– Resistance develops due to MDR pump reducing intracellular Resistance develops due to MDR pump reducing intracellular

concentrations within certain strains of plasmodiumconcentrations within certain strains of plasmodium

In whom is it contraindicated?In whom is it contraindicated?– Contraindicated in psoriasis and porphyriaContraindicated in psoriasis and porphyria

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MefloquineMefloquine

For what is Mefloquine (Lariam) used?For what is Mefloquine (Lariam) used?– Developed by U.S. in the 60s, suppressive and Developed by U.S. in the 60s, suppressive and

clinical cure for multi-resistant strains of P. clinical cure for multi-resistant strains of P. falciparumfalciparum

What is mefloquines mechanism?What is mefloquines mechanism?– Moa: forming toxic complexes with free heme Moa: forming toxic complexes with free heme

that damage the membranes of parasitesthat damage the membranes of parasites

Why not give this drug for long periods?Why not give this drug for long periods?– resitant plasmodium strains are possible, so only resitant plasmodium strains are possible, so only

give for short durations. Only administer orally.give for short durations. Only administer orally.

Page 80: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

PrimaquinePrimaquine

For what is primaquine essential?For what is primaquine essential?– Only effective drug against exoerythrocytic forms (latent Only effective drug against exoerythrocytic forms (latent

hepatic forms), used for radical cure of vivax and ovalehepatic forms), used for radical cure of vivax and ovale

What is Primaquine’s mechanism?What is Primaquine’s mechanism?– “ “unknown but” a metabolite may mediate reactive unknown but” a metabolite may mediate reactive

oxygen production which subsequently damages the oxygen production which subsequently damages the parasiteparasite

What adverse effects are common?What adverse effects are common?– Adverse effects are GI and neutropeniaAdverse effects are GI and neutropenia

For whom is primaquine contraindicated?For whom is primaquine contraindicated?– Contraindicated in glucose-6-phosphate dehydrogenase Contraindicated in glucose-6-phosphate dehydrogenase

deficiencydeficiency

Page 81: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

PyrimethaminePyrimethamineFor what is Pyrimethamine (Daraprim) used?For what is Pyrimethamine (Daraprim) used?– Slow acting drug used in chloroquine-resistant infections. Slow acting drug used in chloroquine-resistant infections.

Can be used for suppressive, but in combination for Can be used for suppressive, but in combination for acute attacks (slow action)acute attacks (slow action)

What is pyrimethamine’s mechanism?What is pyrimethamine’s mechanism?– MOA: inhibition of dihydrofolate reductase resultant in MOA: inhibition of dihydrofolate reductase resultant in

decrease in tetrahydrofolate and Nadecrease in tetrahydrofolate and Na++ synthesis synthesis– Often used with sulfonamides because they have a quick Often used with sulfonamides because they have a quick

onset of action and are synergistic.onset of action and are synergistic.

What is pyrimethamine’s half life and why is this What is pyrimethamine’s half life and why is this important? What adverse effects are common?important? What adverse effects are common?– Half life is 4 days, slow elimination encourages Half life is 4 days, slow elimination encourages

resistanceresistance– Adverse effects can cause folic acid deficiency, stevens-Adverse effects can cause folic acid deficiency, stevens-

johnson syndrome (when combined with sulfadoxime)johnson syndrome (when combined with sulfadoxime)

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QuinineQuinine

For what is Quinine used?For what is Quinine used?– Reserved for clinical cure of severe chloroquine-resitant Reserved for clinical cure of severe chloroquine-resitant

P. falciparum. Not to be given as a sole treatmentP. falciparum. Not to be given as a sole treatment

What is quinine’s mechanism?What is quinine’s mechanism?– Moa: due to properties as a weak base it concentrates in Moa: due to properties as a weak base it concentrates in

food vacuoles of plasmodiumfood vacuoles of plasmodium

What adverse effects are common?What adverse effects are common?– Adverse effects include cinchonism, blood dyscrasia, Adverse effects include cinchonism, blood dyscrasia,

hypoglycemia (very toxic overall)hypoglycemia (very toxic overall)

In whom is quinine contraindicated?In whom is quinine contraindicated?– Contraindicated in afib, myasthenia gravis, tinnitis, optic Contraindicated in afib, myasthenia gravis, tinnitis, optic

neuritisneuritis

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VaccinesVaccines

Vaccines are being developed to prevent Vaccines are being developed to prevent sexual development of parasite in the sexual development of parasite in the mosquito, inhibition of enzyme involved in mosquito, inhibition of enzyme involved in rbc remodeling blocks parasite replication.rbc remodeling blocks parasite replication.– Yes they are.Yes they are.

Page 84: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

Other protozoans: amebiasis,Other protozoans: amebiasis,

How many people are infected with How many people are infected with amebiasis?amebiasis?– 400 million infected, 10 % symptomatic with mild 400 million infected, 10 % symptomatic with mild

to severe dysenteryto severe dysentery

What is the DOC for amebiasis, giardiasis, What is the DOC for amebiasis, giardiasis, and trichomoniasis?and trichomoniasis?– metronidazolemetronidazole

Page 85: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

Trypanosomiasis and LeshmaniasisTrypanosomiasis and Leshmaniasis

What are the two types of What are the two types of Trypanosomiasis? What is the treatment?Trypanosomiasis? What is the treatment?– African and South American (Chagas)African and South American (Chagas)– Nifurtimox is used for ChagasNifurtimox is used for Chagas

What are the three types of Leshmaniasis? What are the three types of Leshmaniasis? What drug is used for each? What drug is used for each?– Three forms, visceral, cutaneous, Three forms, visceral, cutaneous,

mucocutaneousmucocutaneous– Sodium stibogluconate is used for all three Sodium stibogluconate is used for all three

typestypes

Page 86: Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most

ReviewReviewMetronidazole (review)Metronidazole (review)– Drug of choice for trichomoniasis, intestinal and hepatic stages of amebiasis, Drug of choice for trichomoniasis, intestinal and hepatic stages of amebiasis,

and giardiasisand giardiasis– Moa functions as an electron sink in protozoa, the reactive intermediate, Moa functions as an electron sink in protozoa, the reactive intermediate,

then may disrupt DNAthen may disrupt DNA– Contraindicated with alcohol (disulfiram like (oh I think this is actually the guy Contraindicated with alcohol (disulfiram like (oh I think this is actually the guy

who harped on disulfiram-like reactions. Anyway, it’s a good idea to warn who harped on disulfiram-like reactions. Anyway, it’s a good idea to warn people.))people.))

22ndnd line antiprotozoals: What is important for each of these drugs? line antiprotozoals: What is important for each of these drugs?– Emetine and dyhydroemerntineEmetine and dyhydroemerntine

Alternate for amebiasis, no oral form, only i.v. or s.q.Alternate for amebiasis, no oral form, only i.v. or s.q.– NifurtimoxNifurtimox

Reuces severity of actue Chagas diseaseReuces severity of actue Chagas disease– Sodium stibogluconateSodium stibogluconate

DOC for leshmaniasisDOC for leshmaniasis– Diloxanide FuroateDiloxanide Furoate

DOC for asymptomatic amebiasisDOC for asymptomatic amebiasis– QuinacrineQuinacrine

90 % cure rate for giardiasis90 % cure rate for giardiasis