Presentation on theme: "Gastrointestinal System Drugs. Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most."— Presentation transcript:
Intro to fungal infection What are fungi? –Eukaryotes lacking flagella that develop from spores In which patients do most fungal infections occur? –The immunocompromised To what phylum do the causes of superficial fungal infections of skin, nails, and soft tissues belong? What species are common? –Ascomycotina –Trichophyton, Microsporum What phylum causes thrush? –Deuteromycotina (e.g. Candida Albicans) Which two phyla cause systemic fungal infections? –Zygomycotina (Rhizopus nigrans) and basidiomycotina (cryptococcus, histoplasmosis)
Polyenes What are the 2 distinct portions of amphotercin B? –Hydrophobic Macrolide –Polyene (7 trans double bonds) How does amphotericin B work? –Hydrophobic portion binds to ergosterol in fungal cell membrane and forms a pore. This causes ion leakage, disrupts cellular metabolism, and enhances cell mediated immunity. What two ions are leaked out of the pore? –K + and Mg ++ Why doesn’t amphotericin B put holes in human cells? –Human cells contain Cholesterol, while fungal cells contain Ergosterol. This explains the selectivity. Is resistance a problem? –Not right now, but it could occur in the future with mutants with decreased concentrations of membrane ergosterol.
Amphoterrible continued How water soluble and orally available is Amphotericin B? –It is water insoluble, absorption is negligible, and it is 90% protein bound. How do you get a water insoluble solution in IV? –Complex it with Bile salt deoxycholate (0.4 microns colloid/micelles). What are the adverse effects of Amphotercin B? –Fever and Chills, Nephrotoxic, anemia, and rare neurotoxicity and hypersensitivity. What is good about the new amphotercin B formulation? –It’s a lipid reservoir –Decreases in Nephotoxicity. However, its cost is prohibitive. What is the dose range for Amphotericin B? –0.2- 1.2 mg/kg/day What is its main therapeutic use? –It is the treatment of choice (IV) for nearly all life threatening mycotic infections. –Broad spectrum. Can be taken orally or topically for Candida.
Nystatin and Flucytosine Why can’t you use nystatin systemically? –It’s too toxic. How well is nystatin absorbed? –It isn’t absorbed from the GI tract, skin, or vagina. What are the therapeutic uses? –Orally: swish and swallow for candida –Vaginally: insert or cream for candida What is important to remember about Fluctytosine? –Resistance develops very quickly when you use this drug alone. –Never use alone!!! What is the mechanism of flucytosine? –In the fungal cell, flucytosine is converted to 5FU, which inhibitis thymidylate synthesis, which interferes with DNA synthesis. –Mammals do not convert flucytosine to 5FU, thus are unaffected.
Flucytosine continued Describe the pharmacokinetics of Fucytosine. –It is very different from previously covered anti- fungals in that it is well absorbed from the GI tract, crosses the blood-brain-barrier, is widely distributed in the body, and is minimally bound to plasma proteins –Half life is 3-6 hours What are the adverse effects of flucytosine? –Bone marrow suppression, elevation of hepatic enzymes (5% of patients) For what is flucytosine used? –Often combined with amphotericin B, the treatment of choice for cryptococcal and candida meningitis
Imidazoles and Triazoles What is an imidazole? –More toxic compound with 2 nitrogen azole rings What is a triazole? –Less toxic with 3 nitrogen azole rings What is the mechanism of all imidazoles and triazoles? –Inhibits sterol 14-α-demethylase which is involved in formation of ergosterol. This inhibition leads to an accumulation of 14-a-methyl sterols. What are the important things to know about ketoconazole—Class, absorption, distribution, adverse effects, drug interactions, onset of action, half life? –It’s an imidazole –It is absorbed well from GI tract. –Widely distributed but doesn’t cross the BBB –Endocrine abnormalities are the most troubling side effects. Gynecomastia and others. –H2 blockers reduce their absorption by reducing acidic environment. –Slow response time…contraindicated in rapidly progressing fungal infections. –Half life is 8 hours.
Fluconazole and Itraconazole What is different with Fluconazole (from ketoconazole)? –It’s a triazole –Crosses BBB –Greater GI absorption, longer half life (24 hours) –No adverse endocrine effects What are some therapeutic uses for Fluconazole? –Treatment of choice for preventing relapse following successful treatment of cryptococcal meningitis with Amphotericin B. –Vaginal candidiasis? –Prophylactic and acute treatment of oral and esophageal candidiasis in AIDS What is Itraconazole? –A newer more expensive antifungal drug –Less toxic than ketoconazole and has a broader spectrum, but doesn’t cross BBB. What are clotrimazole and miconazole used for? –These older imidazoles are used topically to treat various fungal infections. They are too toxic for systemic use.
Griseofulvin What is the MOA of Griseofulvin? –Inhibits fungal mitosis by producing multinucleated cells. Disrupts mitotic spindle by interacting with polymerized microtubules. –Fungistatic How is Griseofulvin adminstered? –Orally administered and absorbed from the GI tract What happens at high doses? –Will affect mammalian cells. –“…selectivity of action is determined by highest tissue concentration.” What is the disadvantage of Griseofulvin? –Prolonged treatment required. Up to a Year! What are the therapeutic uses? –Griseofulvin is administered orally to treat mycotic infections of skin, hair and nails caused by microsporum, trichophyton, and epidermophyton, but not candida. What adverse effects are noted with Griseofulvin? –Headache, lethargy, confusion, ethanol potentiation, rashes, liver enzyme induction, teratogen and carcinogen.
Terbinafine What is the MOA of Terbinafine? –Inhibition of squalene epoxidase leading to accumulation of sterol squalene, which is toxic to the organism. –Fungicidal What is the advantage of Terbinafine compared to Griseofulvin? –Only have to take it up to 12 weeks, “more effective than griseofulvin.”
Intro to these three lectures There will be 5 questions from gastric acidity, 2 GI questions, and 2 Nausea/Vomiting questions. What are the proton pump inhibitors? –They end in –prazole. Omeprazole, lansoprazole, rabeprazole, pantoprazole, esomeprazole What are the H2 receptor antagonists? –Cimetidine, ranitidine, famotidine, nizatidine. –They end in -tidine What are the antacids? –Sodium bicarbonate, calcium carbonate, Mg ++, Aluminum compounds, and mixtures
Acidity Diseases What are the GI diseases and disorders related to GI acid production (4)? –Dyspepsia, acid indigestion, “heartburn” –Gastroesophageal reflux disease The difference b/w GERD and heartburn is that GERD is recurrent and includes major reflux to such an extent that it can actually cause esophagitis. GERD is due to a relaxed LES. –Gastric and duodenal ulcers –Zollinger-Ellison syndrome (excess gastrin secretion) and hypersecretory states (involve overproduction of gastrin) What two receptors are present on the enterochromafin-like cell that increase that cells release of gastrin? –Histamine type 2 and Muscarinic type 1 receptors
Esophagitis Why do we get acid into the esophagus? –Relaxed LES What are three ways to modulate acid-induced disease? –Inhibit acid secretion –Protect GI mucosa –Neutralize the acid that is secreted What does gastrin do? – 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 cAMP and activates the proton pump to secrete H +. With what is Helicobacter pylori associated? When does infection occur? –Gastric cancer, Gastric/duodenal ulcers, and gastric B cell lymphoma. –Infection is typically acquired in childhood. How is it passed from person to person? –We really don’t know. Maybe oral to oral or fecal-oral What are the diagnostic tests for H. pylori? –Serology, urease breath test, fecal antigen test, endoscopy (expensive/invasive)
Proton Pump Inhibitors What is the mechanism of action of the proton pump inhibitors (PPIs)? –suicide inhibitor of the H+/K+-ATPase (interacts covalently) –Recovery requires synthesis of new enzyme and insertion into the parietal cell membrane; this is why they are long-acting drugs; administered in delayed-release, gelatin-coated capsules, or enteric-coated granules, or enteric-coated tables, or powered drug with sodium bicarbonate. –They are activated in the presence of acid, where they are protonated. Once protonated, the drug is able to react with a free unpaired cysteine in the proton pump. What is the half life of the ppi drugs? –30-90 minutes, but duration of action can be all day (until new enzyme is synthesized). When should PPI drugs be taken? –Before a meal (on an empty stomach with high acidity); they are absorbed better at this time. For what conditions are PPI drugs recommended? –Peptic ulcer disease, dyspepsia, GERD, Zollinger-Ellison syndrome, NSAID induced ulcer
Proton Pump Inhibiting What is the difference between esomeprazole and omeprazole? Which one is more effective? –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 is a little less first-pass metabolism. –They are equally effective. What is the treatment of choice for H. pylori positive gastric/duodenal ulcer disease? What other drug combination is available? –Amoxicillin and Clarithromycin are most effective in addition to a PPI (omeprazole, for instance). –The other combination is PPI + bismuth subsalicylate + tetracycline + metronidazole These two 10-14 day treatment options are considered “permanent” ulcer cures. How do you treat an NSAID-induced ulcer? –use PPIs and reduce, eliminate, or change the NSDAIDs. What side effects are noticed with PPIs? –Rarely nausea, diarrhea, headache, dizziness, bacterial overgrowth in stomach. –New research indicates increased risk of hip fracture in elderly patients on long- term high-dose PPI therapy
Comparasizing Compare H 2 blockers to PPI drugs. –H 2 blockers are used for the same indications as PPIs; they’re not as effective, but they’re great for people with average acid dyspepsia. These act by blocking H 2 receptors on parietal cells. –PPI drugs are better at everything Contrast the metabolism of PPIs to H 2 blockers. –While PPIs are metabolized by the liver, H 2 blockers are excreted unchanged by the kidney. Thus these drugs should not be given to patients with severe renal impairment.
Alternatives Are the PPIs as effective as the H2 antagonists at healing esophagitis? –PPIs are more effective than H2 antagonists at both relieving symptoms and healing esophagitis. By what CYPs are PPIs metabolized? Which one is least metabolized? –PPIs are metabolized by CYP2C19 –rabeprazole is the least metabolized What percentage of people on H2 antagonists report side effects? Which H2 antagonist has anti-androgenic activity? –Less than 3%, sometimes less than placebo patients. –cimetidine What are the antimuscarinics? What is their mechanism? Why don’t we use them much? –Pirenzepine, telenzipine –Block M1 action in ganglia –Their autonomic side effects are much worse than other choices for reducing acid production What are the mucosal protective agents? –Sucralfate (carafate), misoprostol (Cytotec)
Sucralfate, Misprostol, Bismuth What is the mechanism of Sucralfate? What are its side effects and drug interactions? –complex alumninum-sucrose sulfate; –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; activated by acidic environment –few- dry mouth, constipation, decreased bioavailability of TCN, phenytoin, digoxin, cimetidine What is the mechanism of Misoprostol? What is the main problem with misoprostol? –Synthetic analog of PGE1; PGs decrease gastric secretion and increase mucus and bicarbonate secretion. aspirin-like drugs decrease PGs and increase ulcer incidence. –This drug works elsewhere in the body to contract smooth muscle. (contraindicated in pregnancy) Name the colloidal bismuth compounds. What is their mechanism? –Bismuth subgallate, subcitrate, subnitrate, subsalicylate (most common here; PeptoBismol) –Increase mucosal secretion, coat ulcer, thus cytoprotection. Cause detachment of H. pylori from gastric epithelium and lysis of bacterium. Not approved alone for peptic ulcer, no acid-neutralizing activity but does inhibit secretion of gastrin.
Antacids 1 What are the antacids? Can they heal a peptic ulcer? What side effects are common? –Bases that react with stomach acid and neutralize it: Baking soda (NaHCO 3 ), Milk of Magneisa, Calcium Carbonate (CaCO 3 ), Aluminum compounds, and mixtures. –They can heal an ulcer if dosed often enough. –Alkaluria, high Na+ content in some. What are the uses for the antacids? –peptic ulcer, GERD, occasional heartburn What is the basic mechanism of antacids? –bases present in the antacid react with an neutralize stomach acid; decreases symptoms of heartburn and acid-induced pain What general side effects are common with antacids? –alkaluria- may cause kidney stones; sodium content may be high in some preparations, which is dangerous in CHF.
Antacids 2 Why is baking soda not the best antacid? –NaHCO 3 (baking soda) is a highly soluble base that reacts quickly with acid 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 length of action. This is bad. What is the chemical makeup of Tums? –Calcium carbonate (CaCO 3 ) tums. A decent antacid, not well absorbed. It is often recommended for women with occasional dyspepsia with the rationale that the Ca ++ is inherently helpful. Hypercalcemia can be a problem in patients with very poor renal function. 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 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 diarrhea. What is the down side of Aluminum antacids? –Aluminum compounds are very effective but cause constipation. What are the best antacids? –Antacid mixtures of magnesium and aluminum salts are the best antacids: Maalox and Mylanta (best).
Motility and Constipation What happens when the myenteric plexus is activated? –Increases tonic contraction, increases intensity and rate of contractions, increases velocity of contractions The myenteric plexus also promotes release of excitatory mediators proximally (contraction). What are they (3)? –acetylcholine (muscarinic M2 and M3 receptors on GI smooth muscle) –serotonin (5-HT3 and 5-HT4 serotonin receptors) –neuropeptides How might mild consipation be treated in an otherwise healthy person? –no medication needed; increase intake of fiber, fruits, vegetables, complex carbs, bran; exercise; adequate fluid intake laxative administration is appropriate for what? –prevention of straining in patients with hernia, hemorrhoids –evacuation of bowel before surgery, colon procedures (endoscopy) What drugs cause constipation? –drugs causing constipation include phenothiazines, anticholinergics, Ca/Al antacids, and antidiarrheal agents.
Anti-constipants What are the bulk laxative agents? What effect do they have? –hydrophilic colloids, psyllium (Metamucil, Per Diem, many others), agar, bran, methylcellulose –indigestable plant products; dietary fiber and supplements – absorb water and distend the colon, promoting peristalsis. They may increase bloating and gas. first line for chronic constipation What are the osmotic agent laxatives? How do they work? –Any poorly absorbed ion. There are saline cathartics, Mg(OH) 2, MgSO 4, sorbitol, laculose, polyethylene glycol. –These unabsorbed ions pull water into the gut by osmosis. The increased water distends the bowel and stimulates peristaltic contractions. What are the stool softeners and how do they work? –Glycerin and docusate. They allow water to penetrate the stool. What are the stimulant laxatives? –Anthraquinones- aloe, senna, cascara What is the serotonin-4 receptor agonist laxative? How does it work and for what is it (primarily) used? –Tegaserod –Used to activate myenteric plexus and peristalsis, particularly in irritable bowel syndrome.
More constipantagonists What is the cholinomimetic agent laxative? How does it work? For what (specifically) is it used? –Neostigmine (AchE inhibitor). –Enhance gastric, duodenal, and colonic emptying (M3 activation). Has lots of side effects. –Useful for acute large bowel distention. What are the D2 antagonists? How do they work? For what are they primarily used? –metoclopramide and domperidone –D2 antagonists inhibit dopamine’s inhibition of cholinergic action. increase peristaltic amplitude, increase lower esophageal sphincter pressure, enhance gastric emptying, decrease transit time –mostly used as anti-emetics How do macrolides work? –Stimulate motilin receptors on G-I smooth muscle (erythromycin). Rapid tolerance develops. Remember ole Dr. Melchert suffering under these drugs because his mom thought he was allergic to penacillin. What is the chloride channel activators? What is its mechanism? –lubiprostone – recently approved for chronic constipation –increases liquid secretion into the lumen and shortens transit time 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”
D2 Antagonists and Opioids How do the D2 antagonists work? –D2 receptor blocks acetylcholine release. Blocking D2 stimulates Ach release. Stimulating Ach release increases motility. How does Bismuth subsalicylate reduce diarrhea? What other good anti- diarrheal action does it have (microbiologically)? What are its side effects? –inflammatory prostaglandins stimulate diarrhea, inhibitors of cycloxygenase are antimotility Subsalicylate is a mild COX inhibitor –may prevent colonization with foreign E. coli (prevents bacterial binding to mucosa) providing protection from traveller’s diarrhea. –constipating, tinnitus What opioids are used for control of diarrhea? How do they work? –Diphenoxylate and loperamide –Like all opioids, these drugs inhibit pre-synaptic cholinergic neurons in the submucosal and myeteric plexus, which causes increased segmental contractions, decreased propulsive peristalsis, increased transit time, decreased secretions from stomach, pancreas, and intestine, delayed digestion, and increased absorption of Na and water. What are the agents in Lomotil? –Diphenoxylate and atropine. The atropine is added mainly to prevent abuse. Why isn’t loperamide addictive? –It does not cross the blood brain barrier.
Irritable Drugs What is Irritable Bowel Syndrome? –IBS is an idopathic chronic relapsing disorder characterized by abdominal discomfort (pain, bloating, distension or cramps) in association with alterations in bowel habits (diarrhea, constipation or both). Patients note a change in frequency or consistency of their bowel movements. 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. What is the main drug used for irritable bowel syndrome? How does this drug work? –Alosetron –It is a Serotonin-3 antagonist; 5-HT 3 receptors are prevalent on enterochromaffin cells and they mediate bowel induced pain. Also, 5-HT3 receptors exist on enteric cholinergic neurons. Blockade of these receptors inhibits colonic motility. What other drug is good for predominantly constipated IBS? How does it work? –Tegaserod is good for predominantly constipated IBS. –Tegaserod is a 5-HT 4 agonist
Objectives “At the end of this lecture, you should be able to: –Understand the mechanism(s) that control nausea and vomiting. –List drugs used in the prevention of chemotherapy/radiation-induced nausea and vomiting and describe their mechanism of action. –List drugs used in the prevention of post-operative nausea and vomiting and describe their mechanisms.”
Activate Upchuck Where is the vomiting center located? What nerves are involved in emesis triggarization? –The vomiting center is located in lateral medullary reticular formation, close to the fourth ventricle (brainstem) –The vomiting center works through many efferents; it coordinates actions with cranial nerves V, VII, IX, X and XII and spinal nerves to G-I tract, diaphragm and abdominal muscles What triggers the vomiting center? –The chemoreceptor trigger zone (CRZ), located in the 4th ventricle in the area postrema. It is outside the BBB and thus accessible to emetogenic stimuli in the blood or CSF. What kind of receptors exist in the CRZ? –Although the exact mechanism is not well understood, peripheral neuroreceptors and the chemoreceptor trigger zone (CRZ) are known to possess receptors for serotonin, histamine (H1 and H2), dopamine, acetylcholine, opioids, and other neurotransmitters/neuromodulators. –rich in dopamine D2, serotonin 5-HT3 and opioid receptors
All the Anti-emetics on one slide What are the Serotonin-3 receptor antagonists? For what type of emesis do they work? –Ondansetron, granisetron, dolasetron –They work on vegal stimulated emesis (surgery, chemotherapy, and radiation) Name the D2 antagonists. –Metaclopramide, prochlorperazine, promethazine, droperidol Name the antihistamines used for anti-emesis. –Cyclizine and meclazine, Name the antimuscarinic agent used for motion sickness. –Scopolamine Name the cannabinoid used for appetite stimulation and anti-emesis in chemotherapy. –Dronabinol What is the name of the only neurokinin-1 antagonist for N/V? –Aprepitant What two benzodiazepines are used for anticipatory vomiting? –Lorazepam and diazepam What is Nick’s favorite drug of all time? –Phenergan (promethazine). Nausea sucks.
Emetified Terms Define: Nausea and vomiting –A defense mechanism to remove harmful or toxic substances –Unpleasant sensation at back of throat, awareness of urge to vomit, cold sweat, Retching –The gag reflex, the labored spasmodic contractions of respiratory muscles including: The diaphragm, chest wall, and abdominal wall muscles. –Generates pressure gradient leading to vomiting Vomiting –Forceful expulsion of contents
Puke Central Where is the vomiting center? –In the medulla, in the reticular formation, near to the area postrema and chemoreceptor trigger zone The chemoreceptor trigger zone is a circumventricular organ that sits outside the brain and outside the blood brain barrier, it controls the vomiting center. –The vestibular system and balance system has inputs from the cerebellum into this area What are some types of nausea (causes)? –Post op, opioids, chemotherapy, preggers, motion sickness/vestibular disorders, intestinal infection
Serotonin and Dopamine Antagonists What are the 5HT3 antagonists? What are they good for? –Ondansetron, granisetron, dolasetron –Useful to prevent emesis caused by vagal stimulation (surgery), chemotherapy, and radiation Minimal effect on motion sickness nausea –Well tolerated with few side effects What are the D2 antagonists? How does each work? What side effects (effects other than anti-emetic) are noted with each? –Metoclopramide Central dopamine receptor blockade Extrapyramidal side effects; restlessness, dystonia –Prochlorperazine, promethazine Inhibition of dopaminergic, muscarinic, and histaminergic receptors Sedative effect via antihistamine activity –Droperidol Antiemetic via cnetral dopaminergic blockade Antipsychotic and sedative, can cause extrapyramidal effects and hypotension
Anti-emetic Types What type of nausea are the antihistamines and anticholinergics good at treating? What side effects are common with these drugs? –Good for motion sickness treatment, but when used alone they are weak antiemetics –can cause sedation, dizziness, confusion, dry mouth, cycloplegia, urinary retention What are cyclizine and meclizine? For what are they used? –These are first generation H1 antihistamines with anticholinergic effects –Antiemetics for motion sickness or in combination with other agents for opioid and post-operative N & V What is Scopalamine? –An antimuscarinic (anticholinergic), it is the best drug for motion sickness What is Dronabinol? For what is it used? What “adverse” effects are noted? –Delta 9-tetrahydrocannabinol, marijuana –A very good antiemetic and appetite stimulant, used for chemotherapy –Can cause euphoria and dysphoria, What is the mechanism of aprepitant? It is often used in combination with what other drugs? –A Neurokinin 1 receptor antagonist (NK-1), aprepitant blocks the action of substance P. –Aprepitant is often used with a 5-HT 3 antagonist and a corticosteroid. For what type of vomiting are benzodiazepines (lorazepam and diazepam) useful? –Very useful in anticipatory vomiting from anxiety with chemotherapy.
Infectious Diarrhea Why don’t we give antidiarrheals to patients with infections diarrhea? –They can delay clearance of microorganisms and increase risk of invasion. What viral infections cause gastroenteritis? –Rotavirus, norovirus, astroviruses, enteric adenovirus, pestivirus, coronavirus, enteroviruses Yep, they cause it. No real treatments though. What causes of infectious diarrhea do require treatment? –E. Coli (some strains?), salmonella, campylobacter jejuni, Vibrio sp., Yersinia enterocolitica (Europe), Giardia, Cyclospora 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 a conflict regarding treatment. Define enterotoxigenic –Secretes a toxin (which in this case produces a watery diarrhea)
What are some causes of severe diarrhea? –Salmonella, Shigella, Clostridium difficile, Giardia lamblia, cyclospora, Entamoeba histolytica What causes gastrointestinal abscesses? –Enterbacteriaceae (mainly E. Coli), S. Faecalis, Bacteroides fragilis All normal flora? Rank the Gi antibiotic drugs in order of most used to least used (8). –Fluoroquinolones, sulfamethoxazole trimethoprim, nitroimidazoles, vancomycin, penicillins, monobactams, cephalosporins
Fluoroquinolones What is the mechanism of fluoroquinolones? –Inhibition of DNA gyrase (Topo 2) and Topo 4. Addition of a flourine expands range of action. –Bind Topo 2 with high affinity. Topo 2 is required for DNA synthesis and transcription for unwinding. –Topo 4 is also inhibited. Topo 4 breaks the chains that are created when bacterial chromosomes replicate (Decatenation). Inhibiting Topo 4 inhibits DNA synthesis. How selective are fluoroquinolones? –They have a much higher affinity for bacterial Topos than human Topos. However, they still have side effects that are unrelated to topoisomerase inhibition. What are the mechanisms of resistance(2)? –Random point mutations in topoisomerases that produce an enzyme with a lower affinity for the drug –Drug efflux pumps that pump the drug back out. –Plasmid mediated resistance is “unlikely.” These compounds are synthetic and do not have analogues in nature.
Fluoroquinolones continued What is the spectrum of activity of flouoroquinolones? –Have a wide spectrum, but they generaly have poor actiivity against anaerobes like: bacteroides fragilis, propionibacterium acnes, peptococcus, peptostreptococcus, What is the main absorption problem with fluoroquinolones? –Ca ++ or Mg ++ may decrease absorption through chelation For which pathogens are fluoroquinolones the DOC? –Enterotoxigenic E. coli, Shigella, salmonella, vibrio, Campylobacter jejuni What are the adverse effects of fluoroquinolones? –Generally better tolerated than bactrim –CNS stimulation (GABA inhibition), photosensitivity, GI discomfort with N/V –Accumulate in connective tissues (those high in Ca) and produce arthropathy and arthralgia, risk of tendon rupture in children. –Hematological toxicity has kept many off the market. –Prolonged QT interval with torsades des pointes
Fluoroquinolone groups With what do fluoroquinolones interact? –Antacids, dairy products, multivitamins –Inhibition of CYP 1A2 (theophyllines and cipro) Combined with inherent stimulant effects can cause marked CNS stimulation How often do we use Group 1 Fluoroquinolones? –Almost never, norfloxacin for urinary problems Which group do we use for GI? Name some (3). –Group 2s, which are good for enterobacteriaceae, –Ciprofloxacin, ofloxacin, lomefloxacin More likely to inhibit GABA and CYP 1A2 For what are Group 3 good? Name some (3). –They have much better (ideal even) pharmacokinetics and they inhibit P450 and GABA much less. They are potent against a wide variety of organisms. Their spectrum includes all of the second generation’s bugs plus more. –Levofloxacin, Moxifloxacin, gemifloxacin
Bactrim Why do sulfonamides and trimethoprim work well together? Why is this combination selective for bacteria over humans? –Its synergistic, sulfonamides inhibit the formation of dihydropteroic acid while trimethoprim inhibits dihydrofolate reductase. (2 steps in the same pathway) –Bacterial cells synthesize their own folic acid, whereas humans recycle folic acid. What is the spectrum of Sulfamethoxazole-Trimethoprim? –Strep, staph, Neisseria, Moraxella, most enterobacteriacease (including yersinia), H. Influenza, Legionella, Listeria monocytogenes, pneumocystis –E. coli? What is a nonpharmacologic reason to use sulfamethoxazole-trimethoprim? –Pharmacoeconomics
Sulfamethoxazole-Trimethoprim adverse effects What adverse effects are common with Sulfamethoxazole-Trimethoprim? –Similar to slufonamides alone, adverse effects are 75% dermatological (rash!) –Crystalization in the urine is another problem because the pKa are often above 7 Sulfisoxazole is more water soluble, but its half life is not as good as sulfamethoxazole. So we use sulfamethoxazole with trimethoprim for half life purposes –Hematologic: rare agranulocytosis and hemolytic anemia –Most are highly protein bound (drug interactions)
Metronidzole When is metronidazole used? –Good for anaerobic coverage. Often used with diverticulitis. What is the mechanism of metronidazole? –The nitro group accepts electrons (from electron- transport), a reactive intermediate is formed, DNA and phospholipid are damaged. –Bactericidal Why is it selective? –Mammalian cells utilize oxygen as the final electron acceptor in electron transport. Cancer cells are more anaerobic (and thus more suceptible), but you can’t use it as an anti-cancer drug because the dosage (and toxicity) is too high. What is the spectrum of metronidazole? –Bacteroides fragilis, clostridium, helicobacter
Metronidazole What are the adverse effects of metronidazole? –Most common are n/v, headache, dry mouth, metallic taste –Disulfiram like reaction He harped on this (or maybe it was someone else, but someone harped on it), make damn sure you warn your patients about disulfiram-like reactions. All humans are alcoholics. –Rare CNS disturbances –It is a possible mutagen What is different about Tinidazole? –Consider it the same (as metronidazole) for this course
Vancomycin What class is Vancomycin? –Vancomycin is a glycopeptide NOT an aminoglycoside. What is its mechanism? For what GI bug might you use Vancomycin? –Binds with high affinity to the d-alanyl-d-alanine terminus of the peptidoglycan precursors and inhibit cross-linking. Thus, a cell wall inhibitor –It has great activity against Clostridium difficile. What percentage of vancomycin is absorbed orally? –None, but we can give it orally and get minimal adverse effects. It still treats clostridium difficile (orally).
I don’t know a title for this slide What is the best database for determining the acting agent during a poisoning? –Your friendly local poison center 1-800-3poison What are the initial considerations you should always include when dealing with an emergently poisoned person? –Ensure airway, cervical spine protection, ventilation, and circulation. What do you do for a person with acute mental status changes in the ER? –If you can’t disprove hypoglycemia, give some glucose. Give oxygen. If alcoholic, add thiamine. –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 to. Just handle the airway if possible. –Handle the ABCs. (airwaybreathingcirculation) What two drugs do you never give to an unconcious person? –Physostagmine and flumazanil (benzo antagonist), the latter because of withdrawal and seizure precipitation.
Toxic Syndromes What are toxic syndromes? –These are “poisoning patterns” that are useful if you can spot them. Describe anticholinesterase/cholinergic syndrome? –Stimulating the parasympathetic and sympathetic nervous system at the same time causes: SLUDGE + unconcious, normal BP –(Salivation, Lacrimation, Urination, Defecation, Gastrointestinal cramping, Emesis) Also sweating, miosis, wheezing, bradycardia, general parasympathetic excess signs Now I guess I’m gonna writeup the other syndromes. They’re kind of cool I guess and good to know for life and medical practice. Go over it or skip it, I don’t care.
Syndromes Describe extrapyramidal syndrome. What causes it? –Movement disorders, rigidity, tremor, torticolis, opisthotonus, etc. –Caused by dopamine antagonists (butyrophenones and phenothiazines) and mimicked by strychnine and tetanus Describe anticholinergic syndrome. What causes it? –Mydriasis, dry (mouth), dysphagia, blurred near vision, tachycardia, hypertension –Caused by atropine, scopolamine, tricyclic antidepressants in overdose, jimson wed and some mushrooms Describe hemoglobinopathy syndrome. What causes it? –Hypoxia, headache, disorientation, coma, n/v, cardiac dysfunction, acidosis and death –Carbon monoxide toxicity or methemoglobinemia Describe metal fume fever (this is really interesting). What causes it? –Influenza-like: chills, n/v, myalgia, fever, leukocytosis, cough, respiratory distress. –Happens in foundry workers, welders, etc. who inhale fumes.
More syndromes Opioid syndrome. –Pinpoint pupils, respiratory depression and hypotension. You can use naloxone, but be careful because withdrawals are tough and they make the patient hard to deal with –Believe it or not, this syndrome is caused by opioids Sympathomimetic excess syndrome. –Nervousness, tremor, diaphoresis, CNS excitation, hypertension, tachycardia, and seizures Diaphoresis, prescence of bowol sounds, and lack of urinary retention together are pretty specific and help you rule out anticholinergic poisoning or hypoglycemia –Cause not listed (my guess is epi or cocaine) Withdrawal syndrome. –Anxiety and drug seeking behavior. Opioid withdrawal has mydriasis, piloerection,rhinorrhea, and lacrimation. Non-opioid depressants have more severe withdrawal (as you know) and can have seizure, hallucinations, and hyperpyrexia. –Obvious cause. Serotonin Syndrome. –Hyperreflexia, spasticity, hypertension, hyperthermia, altered mental status –Many things can cause excess serotonin
What causes what? What does a wide QRS indicate (that the patient has toxicly ingested)? –Any sodium channel blocker What causes sinus tachycardia? –A million things: fear, anger, excitement, stimulants, hallucinogens, hypoglycemic, pain. What causes sinus bradycardia? –Beta blocker, calcium channel blocker, cholinergics, and digitalis. What causes metabolic acidosis? –Aspirin, methanol, ethylene glycol What causes GI dysfunction? –Non-specific, (anything) What does he do when he sees someone with altered mental status? What can cause altered mental status? –Use a benzodiazepine, probably lorazepam or diazepam. –Infection, tumors, metabolic problems (thyroid, calcium, CO2, sugar), withdrawal, poison, heat/cold, primary psychiatric problem
More information without a unifying pattern or theme of any kind What drug class should be used for seizures? What causes toxicologic seizures? –Benzodiazepines –Global cortical dysfunction, which is why phenytoin is not useful. What tests should be run in all non-trivial toxicology cases? –Electrolytes, BUN, creatinine, glucose, arterial blood gases, liver function 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 levels useful? –They are useful to confirm an existing suspicion –Lithium, dig, aspirin, methanol, ethylene glycol, theophylline, salicylate, acetominophen For what are x-rays good in a toxified patient? –Tell you about heart size, lung infiltrate, condoms full of cocaine. Is it a good idea to run a gastric decontamination? –This is an incredibly contentious idea with minimal consensus –It is a bad idea to reflexively do any of these (to do them without thinking on any patient): charcoal, lavage, ipicap, flushing.
Gastric decontamination Name two decontamination procedures that are pretty well universally accepted and a good idea. –Copious irrigation for something in the eye, soap and water for skin contamination. How awesome is Syrup of Ipicac? –No utility in the ER, can be really bad if you have ingested something sharp –Was one of the most ridiculous Family Guy scenes ever, however. Family Guy scenesFamily Guy scenes How awesome is the olde stomach pump (gastric lavage)? –Very rarely useful. Only if you have a big reason to believe there is a bunch of stuff still in the stomach. How about some charcoal? –More useful, but still dangerous and only useful when recent (2 hour) ingestion. What about flushing out the GI tract? –This works by having the person drink the hell out of some MiraLax (osmotic diarrheal agent). They hate you and the nurses hate you.
Specific Curatives What would you give if you ever saw someone with iodine poisoning? –Starch How does one acquire hydroflouric acid poisoning? How does this poisoning work? How is it treated? –Don’t use gloves when cleaning copper? –Flouride complexes the calcium, causes neural irritability in the fingertips. Causes intense pain. –Give calcium gluconate topically, locally (arterially) When should you use dilution (give fluids orally)? –Probably never, it often makes things worse.
Antidotes! Give the antidote for each toxicant. Iron –Deferoxamine Organophosphates –2-pam chloride and atropine Cyanide –Amyl nitrite, sodium nitrite, and thiosulfate –Or hydroxycobalamin Opiates –Naloxone or naltrexone Carbamates –Atropine Methanol or Ethylene glycol –Ethanol or 4-methyl pyrazole Carbon monoxide –Oxygen, hyperbaric oxygen Tricyclic antidepressants –Sodium bicarbonate
Elimination Mechanisms What are some ways to get rid of a pre-absorbed toxicant? –Ion trapping in urine –Charcoal administration Sucks toxicant out of the bowel –Hemodialysis Low molecular weight, non-protein bound, water soluble toxicants –Plasmapheresis and exchange perfusion When would you consider these? –When it can be removed and the patient is deteriorating or not responding to supportive care, or if you know it’s going to get bad later. –Or if you have impairment of the normal excretory route (like kidney failure)
Snakes on a Plane 30 species of poisonous snakes in the U.S. Most bites in the U.S. are ___. –Pit viper bites. (copper head cotton mouth, rattlesnakes. They all have a pit that is sensitive to heat) Most bites in Arkansas are ____. –Copperhead bites, which are not as bad as cottenmouth, which are not as bad as rattlesnakes. Describe Pit Vipers –Depressed (pit) areas behind their paired nostrils act as heat sensing organs. They have triangular heads, elliptical pupils, and paired yellow hypodermic fangs. –Copperheads have red heads, cottonmouths have white oral mucosa, and rattlesnakes have rattles
Behavior Describe the behavior of: –Rattlesnakes Smart, don’t want to bother you. They will give you an opportunity to not get bitten. –Cottonmouths Aggressive, obnoxious creatures –Copper head An indolent, lazy creature. Won’t do anything. Describe Coral snakes (rare bites in AR). –12-18 inches long, red, yellow, and black bands. Red to yellow, round black head, round pupils. No fangs, they bite and chew on you. Not to be confused with king snakes, red on black, red snout
Venom Features of venemous snake bites –Bigger snakes have more venom, number of bites, how deep the bite is, location of the bite. –Pit vipers leave puncture wounds. Usually two, but can be one or ten. Some bites are dry (20-30%). Some punctures are not snake bites. –Coral snakes (and some others) just leave scratches Compare the severity of each snakes venom. –Rattlesnake > cottonmouth > copperhead. Coral snakes are different (curare-esque), but very toxic. Venoms –Once injected, they bind to tissue and also circulate. Only the circulating venom can be neutralized. Arkansas pit vipers are neurotoxic, but not significantly. –Usually get a lot of swelling. –Rhabdomyalisis is a common problem and can cause renal failure through myoglobin release.
Snake Symptoms What are the symptoms/signs present after pit viper bites (crotaline venom)? What lab values? –Immediate pain, hemorrhagic blebs, and swelling occur. Swelling continues to worsen while myonecrosis and rhabdomyalisis occur. Symptoms can take hours to develop –Systemic symptoms may include weakness, nausea, restlessness, paralysis, and renal failure. –INR, PT, PTT all go up. DIC can occur. Can allergic reaction to a snake bite occur? –Yes How do you grade pit viper invenomation? –Dry bite, grade 0 2 puncture wounds, little pain, no swelling, watched for 8-10 hours –Mild invenomation Puncture wounds, some swelling, no systemic symptoms –Moderate Invenomation Local wound, hemorrhages, bullae, dramatic swelling extending well beyond site of bite. Systemic signs: anxious, pain, altered mental status. Abnormal lab findings. Urine myoglobin. Stable vital signs –Severe invenomation Local wound with dramatic swelling, as above but cardiovascular instability
Coral Venom Describe coral snake invenomation. –Usually on the hand, you have to try to get bitten. They bite and chew, salivate the venom. –Significant delay until onset of symptoms, 40% dry bites. 12 or more hours may pass before symptoms occur. –Competitive neuromuscular blocker. Paralysis, Hypoventilation respiratory acidosis occur.
Cox vs. Turk When is surgery a possible application? –Usually when bite is on a digit, face, tongue, or neck. Otherwise snakebite is a medical illness with surgical complications. –The surgery/medicine rivalry can be ridiculous. If you treat early enough, surgery is usually unnecessary. However, there are three cases where surgery is useful: Badly invenomated digit If a compartment syndrome is developing: –Rising pressure from swelling blocks off the blood supply. You need to make sure that the pressure is actually high and blocking blood flow, because sometimes huge swelling can have low pressure and thus be non-surgical. If compartment syndrome does occur, surgeons can cut the fascia and restore blood flow. Necrotic tissue may need to be debrided, reconstructive surgery may also be necessary
Hospitalization When should you admit patients to the hospital? –With a viper bite, hospitalize overnight regardless of symtpoms. What should you do outside the hospital? –Immobilize the bite site and get their ass to the hospital. Don’t use a tourniquet, unless it just blocks lymphatics (especially not for pit vipers because it will keep the venom localized and make them lose the extremity). Don’t use ice. Go to the hospital. 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 want it to be in a helicopter.
Treatment options When should you start adding coagulation factors and platelets? –After administering anti venom (otherwise venom will just eat the new coagulation stuff) Who needs antivenom? –Must have some systemic symptoms or severe local effects, swelling at the site. –If you aren’t sure, call the poison center. What antivenom does one use for pit viper bites? How do you administer it? –CroFab, a polyvalent antivenom derived from sheep –Keep giving vials until their coagulation stabilizes, then two vials every six hours for three dosings (24 hour total dosing). What do you do if they might have been bitten by a coral snake? –Play no games. –Give antivenom, put them in the ICU, keep them there for at least day or two. Antivenom is a highly antigenic horse serum, so watch out.
Worm types What is the most common cestode? –Taenia saginata (beef tapeworm) is the most common tapeworm. What is the most common nematode? –Ascaris lumbricoides is the most common roundworm. What is the most common trematode? –Schistosoma mansoni (blood fluke) is the most common fluke.
Jump right in Severity of helminthic infection is determined by what? –Extent of initial exposure For what is Niclosamide (niclocide) used? –Drug of choice for most cestode infections ON TEST What is niclocide’s mechanism? How well does it kill adults? Ova? –Inhibition of glucose uptake and energy production from anaerobic metabolism in the parasite, resulting in detachment from the intestinal wall and evacuation by normal peristalsis –Lethal effect kills adults but not ova So consider purging the GI tract after treatment to prevent migration (cysicercosis) –House pilot episode: neurocysticercosis What is cysticercosis? –Larvae invade intestinal wall and lodge in other tissues (like the brain) How is it administered? What side effects are common? –Taken orally –Adverse effects are few, abdominal discomfort happens.
Praziquantil What is Praziquantil used for? –It is often considered the drug of choice for all cestode and trematode infections What is the mechanism of Praziquantil? –Increases permeability of worm cell membrane to Ca ++ ions. Influx of calcium produces a massive contracture and impairs their ability to attach to the intestinal wall. –Slightly higher doses also produce tegumental damage to the worm which activates host defenses. Describe the pharmacokinetics of praziquantil. –Taken orally, absorbed well, extensive first pass metabolism What adverse effects are common? –abdominal discomfort, fever, sedation, headache
Benzimidazoles For what are benzimidazoles used? –Drugs of choice for most infections produced by nematodes –They are broad spectrum, though specific drugs may be preferable for specific organisms What is the mechanism of Mebendazole (Vermox)? Is it useful for adults or ova? For what bug is it useful? –Inhbibition of helminth glucose uptake resulting in reduced glycogen and ATP levels. Also inhibits microtubule polymerization by beta- tubulin Helminth selectivity is achieved because of higher affinity for helminth targets –Lethal effect extends to both adults and ova, therefore no need to purge –Drug of choice for pinworms (E. vermicularis). Reinfection with pinworms is common, so family members should also be treated. What is the treatment for pinworms? –Mebendazole and possibly an anti-itch cream.
Thiabendazole What is the mechanism of Thiabendazole? –Mechanims is similar to but different from mebendazole in that it (also) inhibits fumarate reductase which is essential for anaerobic metabolism of helminths What life cycle forms does thiabendazole kill? –Kills adult and ova, but larvae from T. spiralis in tissues is not killed How is thiabendazole absorbed? –Rapidly absorbed in the GI tract What side effects are common with thiabendazole? –Big side effects, usually prevent use for GI infections n/v, diarrhea, vertigo, crystalluria, leukopenia, stevens-johnson syndrome For what is thiabendazole used? –Generally used topically for cutaneous larva migrans (creeping eruption) often seen with Strongyloides stercoralis infections.
Albendazole What is Albendazole? For what is it used? –A newer benzimidazole available for “compassionate use” from smithkline beecham –Drug of choice for neurocysticercosis and hydatid disease
Pyrantel Pamoate (antiminth) For what is pyrantel used? –Drug of choice for several nematode infections (hookworm) How does pyrantel work? –Depolarizes the myoneural junction of helminth muscle via cholinesterase inhibition to cause spastic paralysis Worms are passed alive, with little chance of absorption of disintegration products –Affinity for mammallian acetylcholinesterase is much less than that for helminths What adverse effects are common? –Adverse effects include GI symptoms, fever, CNS effects due to nicotinic actions Contraindications? –Contraindicated in pregnancy, children under one year old, or with piperazine
Less used Anihelmintic drugs “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: Piperazine (vermazine) –Acts as an inhibitory neurotransmitter helminth analogue producing hyperpolarization and flacid paralysis\a lumbricoides and e vermiculoaris Ivermectin –Drug of choice for nematode O. volvulus (“river blindness”) Diethylcarbamazine –Drug of choice for exotic nematode infections, W. bancrofti, B. malavi, and L. Loa –Often introduced into table salt at 0.4% Metrifonate (bilarcil) –Low cost, used for treatment of urinary shistosomiasis in Africa –Organophosphorus inhibitor of cholinesterase Oxamiquine –Alternate drug for treatment of trematode S. mansoni infections Bithionol –Drug of choice for treatment of trematode F. hepatica –Available from the CDC only
Malaria How many people are “affected” by malaria? –2.4 billion (40%) of the population Which two species of malaria produce secondary liver forms which cause relapses of clinical symptoms (dormant in the liver)? –P. vivax and P. ovale What are the four categories of chemotherapy for malaria? –Prophylaxis- prevention of a clinical attack by prevention of the erythrocytic stage DOC Mefloquine (in areas with chloroquine resistance) Chloroquine can be used if no resistance, doxycycline (2 nd choice) and pyrimethamine plus sulfadoxine (3 rd choice) are alternatives –Clinical Cure- interrupts erythrocytic stage and terminates attack DOC is mefloquine (unless chloroquine sensitive) Secondary choice is Quinine, 3 rd choice is pyrimethamine plus sulfadoxine –Radical Cure- eliminates all parasites from body P. vivax and P. ovale: –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. 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 infection –Gametocidal therapy- destroys sexual forms in blood Falciparum: primaquine Vivax and malariae: chloroquine
Chloroquine For what is Chloroquine (Aralen) used? –Developed by Nazi Germany, it is the drug of choice for suppressive treatment and acute uncomplicated attacks, if not resistant Why is chloroquine a pretty good antimalarial? –Effective against erythrocytic forms, is fast acting (1-2) days, most versatile antimalarial drug What is chloroquine’s mechanism? –Moa: blocks transcription and accumulates with plasmodium How is it administered? –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 building up in the plasma How does resistance occur? –Resistance develops due to MDR pump reducing intracellular concentrations within certain strains of plasmodium In whom is it contraindicated? –Contraindicated in psoriasis and porphyria
Mefloquine For what is Mefloquine (Lariam) used? –Developed by U.S. in the 60s, suppressive and clinical cure for multi-resistant strains of P. falciparum What is mefloquines mechanism? –Moa: forming toxic complexes with free heme that damage the membranes of parasites Why not give this drug for long periods? –resitant plasmodium strains are possible, so only give for short durations. Only administer orally.
Primaquine For what is primaquine essential? –Only effective drug against exoerythrocytic forms (latent hepatic forms), used for radical cure of vivax and ovale What is Primaquine’s mechanism? – “unknown but” a metabolite may mediate reactive oxygen production which subsequently damages the parasite What adverse effects are common? –Adverse effects are GI and neutropenia For whom is primaquine contraindicated? –Contraindicated in glucose-6-phosphate dehydrogenase deficiency
Pyrimethamine For what is Pyrimethamine (Daraprim) used? –Slow acting drug used in chloroquine-resistant infections. Can be used for suppressive, but in combination for acute attacks (slow action) What is pyrimethamine’s mechanism? –MOA: inhibition of dihydrofolate reductase resultant in decrease in tetrahydrofolate and Na + synthesis –Often used with sulfonamides because they have a quick onset of action and are synergistic. What is pyrimethamine’s half life and why is this important? What adverse effects are common? –Half life is 4 days, slow elimination encourages resistance –Adverse effects can cause folic acid deficiency, stevens- johnson syndrome (when combined with sulfadoxime)
Quinine For what is Quinine used? –Reserved for clinical cure of severe chloroquine-resitant P. falciparum. Not to be given as a sole treatment What is quinine’s mechanism? –Moa: due to properties as a weak base it concentrates in food vacuoles of plasmodium What adverse effects are common? –Adverse effects include cinchonism, blood dyscrasia, hypoglycemia (very toxic overall) In whom is quinine contraindicated? –Contraindicated in afib, myasthenia gravis, tinnitis, optic neuritis
Vaccines Vaccines are being developed to prevent sexual development of parasite in the mosquito, inhibition of enzyme involved in rbc remodeling blocks parasite replication. –Yes they are.
Other protozoans: amebiasis, How many people are infected with amebiasis? –400 million infected, 10 % symptomatic with mild to severe dysentery What is the DOC for amebiasis, giardiasis, and trichomoniasis? –metronidazole
Trypanosomiasis and Leshmaniasis What are the two types of Trypanosomiasis? What is the treatment? –African and South American (Chagas) –Nifurtimox is used for Chagas What are the three types of Leshmaniasis? What drug is used for each? –Three forms, visceral, cutaneous, mucocutaneous –Sodium stibogluconate is used for all three types
Review Metronidazole (review) –Drug of choice for trichomoniasis, intestinal and hepatic stages of amebiasis, and giardiasis –Moa functions as an electron sink in protozoa, the reactive intermediate, then may disrupt DNA –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 people.)) 2 nd line antiprotozoals: What is important for each of these drugs? –Emetine and dyhydroemerntine Alternate for amebiasis, no oral form, only i.v. or s.q. –Nifurtimox Reuces severity of actue Chagas disease –Sodium stibogluconate DOC for leshmaniasis –Diloxanide Furoate DOC for asymptomatic amebiasis –Quinacrine 90 % cure rate for giardiasis