Final Flashcards
What are the initial non-pharmacologic and pharmacologic priorities when treating a patient with an overdose?
Stabilization:
- ABC management
- Vital signs
- IV access
- Oxygenation
Exposure:
- Medications/illicit substances
- Doses
- Time of ingestion
- Family/EMS report
- Pill count
Assessment:
- Physical exam
- Labs (BMP)
- APAP/salicylate concentrations
- EtOH/toxic alcohol panel
- Decontamination?
- Antidote?
What is the equation to calculate anion gap?
(Na + K) - (Cl + HCO3)
Gap is present if greater than 14
What is the equation to calculate osmolar gap?
Gap = measured - calculated
Calculated = (2 x Na) + (BUN/2.8) + (glu/18) + (EtOH/4.6)
Gap is present if greater than 10
What are the characteristics of these decontamination strategies: activated charcoal, cathartics, gastric lavage, whole bowel irrigation, hemodialysis
activated charcoal - used to prevent absorption.
- Pros: decreases time related problems, absorbs most toxins
- Cons: difficult administration, should not be administered if the airway is unprotected
cathartics - decrease GI transit to help eliminate the substance
- ex. Magnesium citrate, sorbitol
- don’t use commonly, not recommended
gastric lavage -
- use with ingestion of large amounts of substances, if the substance has a high morbidity rate, if activated charcoal doesn’t work, or if they have a jeopardized airway
- Pros: difficult to refuse, comatose patients, use with other agents
- Cons: can cause complications like vomiting aspiration, mechanical injury
- contraindicated in: ingestion of corrosives or hydrocarbons, or depressed gag reflex
whole bowel irrigation: very rare
- use if pt can’t do lavage and if charcoal didn’t work; if they ingested sustained-release products, “body packers/stuffers”, iron, etc.
- continue until the presence of clear rectal effluent
- give through NJ tube due to large volume of PEG needed
hemodialysis:
- use if none of the other methods work or in renal/hepatic failure
- effective for alcohols, lithium, salicylates, and theophylline
What toxicity signs and symptoms are seen in opioid toxicity?
- respiratory depression
- nausea and vomiting
- pinpoint pupils
- drowsiness
- bradycardia
- hypotension
What is the most common agent used for opioid toxicity?
Naloxone - 0.4-2mg IV push, IM, IN
- use lower doses in pts with chronic opioid dependence to avoid withdrawal
- use higher dose in patients with suspected illicit drug use (synthetic opioids)
- consider continuous infusions with longer acting opioids if there’s prolonged signs/symptoms
What is a toxic dose of APAP? What are the high risk and protective conditions for APAP toxicity?
toxic dose: 7.5-15g, can be lower
high risk: malnutrition/chronic illness, concomitant CYP2E1 inducers (isoniazid), chronic alcohol ingestion
protective conditions: acute alcohol ingestion, children
What is the toxic metabolism of APAP?
If the glucuronyl transferase and sulfotransferase pathways of APAP metabolism are saturated, APAP will be metabolized by CYP2E1, which produces NAPQI. NAPQI can be metabolized by GSH transferase to mercapturic acid (not harmful), or go through covalent binding, which results in necrosis.
In 72-96hours, peak AST/ALT levels will be reached, resulting in hepatic encephalopathy, renal failure, and death
What are the main treatment options for APAP toxicity?
NAC: Glutathione analogue that serves as a glutathione surrogate, which can inactivate the toxic APAP metabolite.
- need to obtain APAP concentration at least 4 hours post-ingestion, then look at Rumack-Matthew Nomogram for NAC dosing.
- Most effective when started w/in 8 hours of ingestion
- Preferred to be given IV (3 dose regimen)
Activated charcoal: recommended within the first 4 hours of ingestion
- 1g/kg PO once
- No effect on NAC
What are the toxicity risk factors with salicylate toxicity?
Mixed acid/base disorders: increased anion gap -> metabolic acidosis, early respiratory alkalosis -> hyperventilation
Electrolyte disturbances: hypokalemia, hypo/hypernatremia
Salicylate concentrations:
- 10-15: analgesic properties
- 15-20: anti-inflammatory
- >30: mild toxicity (dizziness)
- > 80: CNS effects
Signs/symptoms: tinntus, vertigo, decreased GI motility, AMS, seizures, lethargy/coma, nausea and vomiting
What is the main salicylate antidote?
Sodium bicarbonate: causes urine alkalinization
- indicated if serum salicylate level is > 30, anion gap metabolic acidosis, or AMS
- 1-2mEq/kg IV push over 1-2 mins
- Monitor serum pH and electrolytes
What are the signs and symptoms of sedative toxicity?
CNS depression, respiratory depression, hypotension, bradycardia
What are our options for sedative toxicity?
Flumazenil: competes with BZDs at the BZD binding site of the GABA complex
- use with caution in pts with seizures, since it can induce seizure activity
- not typically used
What are the toxicity signs and symptoms for TCAs?
AMS, hypotension, tachycardia, prolongs QRS, seizures, anticholinergic symptoms
QRS > 100: increased risk of seizures
QRS > 150: increased risk of cardiac arrhythmias
What is the antidote to TCA toxicity?
Sodium bicarbonate - increases sodium gradient of poisoned sodium channels
- indicated if QRS interval > 100ms, TCA induced arrhythmias or hypotension, or metabolic acidosis
- 1-2 mEq/kg IV push over 1-2 mins
- monitor serum pH
- d/c when QRS interval is < 100ms, resolution of ECG abnormalities, and hemodynamically stable
What are our options for seizure management in TCA toxicity?
- benzodiazepines
- phenobarbital
- maybe phenytoin, fosphenytoin, levetiracetam? these target sodium channels so we don’t know how effective these will be
What are the signs and symptoms of antipsychotic toxicity?
Neuroleptic malignant syndrome (NMS), extrapyramidal symptoms (EPS), hypotension, sedation, tachycardia, QT/QRS prolongation
- toxic doses not well defined
- symptoms usually seen within 1-2 hours of ingestion
- peak symptoms in 4-6 hours
- duration is roughly 12-48 hours
How do we manage the extrapyramidal symptoms of antipsychotic toxicity?
benzotropine 2mg IM
- onset 15-20 mins
- longer 1/2 life
diphenhydramine 1-2mg/kg IV/IM (up to 50mg) over several minutes
- onset 5 mins
- continue with oral therapy for 3-4 days (diphenhydramine 50mg PO TID)
How do we manage neuroleptic malignant syndrome in antipsychotic toxicity?
worried about hyperpyrexia. this occurs 3-9 days after initiating therapy or after adding a second agent.
- haloperidol, depot fluphenazine, or chlorpromazine are the most common offending agents
- death secondary to rhabdomyolysis, renal failure, arrythmias, etc.
- causes higher fever (than serotonin syndrome), lasts > 24 hours, causes diffuse lead pipe rigidity
- Stop the agent
- do rapid external cooling
- benzodiazepines
- dantrolene
- bromocriptine
What are the triad of symptoms for serotonin syndrome? How do we manage serotonin syndrome in antipsychotic toxicity?
- triad of symptoms: AMS, autonomic instability, neuromuscular abnormalities
- development of serotonin syndrome is rapid (within 6 hours)
- lasts <24 hours, lower limbs are more affected than upper limbs
- Stop the agent
- benzodiazepines
- aggressive cooling
- cyproheptadine (periactin): 1st gen histamine receptor blocking agent
What are the signs and symptoms of digoxin toxicity?
Non-cardiac:
- nausea/vomiting
- abdominal pain
- anorexia
- confusion
- vision changes
cardiac:
- bradycardia
- 2nd or 3rd degree heart block
- arrhythmias
- hyperkalemia
How do we manage digoxin toxicity?
- D/C digoxin
- administer activated charcoal if presentation within 2 hours of ingestion
- hemodialysis is not effective
- consider digibind
Digibind (digoxin immune fab): binds free digoxin and tissue bound digoxin released during equilibrium state
- indicated for ventricular arrhythmias, bradycardia, 2nd, or 3rd degree heart block that’s not responsive to atropine
- hyperkalemia (>5.5) with s/sx of toxicity
- serum concentrations > 10-15 drawn at least 6 hours after time of ingestions
- ingestion > 10mg in adults, >4mg in children
- dose by vials based on milligrams of digoxin ingested or serum digoxin concentration
- after administration of digibind, serum digoxin concentrations are useless
What are the signs and symptoms of CCB and BB toxicity?
CCB:
- hyperglycemia
- metabolic acidosis
- pulmonary edema
- ileus (SR)
BB:
- hypoglycemia
- bronchospasms
both:
- hypotension
- bradycardia
- arrhythmias
- cardiogenic shock
- CNS depression
What are the potential antidotes to CCB or BB toxicity?
atropine - blocks parasympathetic activity to increase the heart rate
- use when bradycardia
- not usually effective in CCB and BB overdoses
calcium - enters open voltage sensitive calcium channels to promote calcium release, resulting in myocardial contractility
- more effective in CCB v. BB
- calcium chloride has 2x more elemental calcium vs. gluconate, but extravasation is more likely with chloride form
vasopressors - binds to beta receptors and Gs receptors to stimulate cAMP and calcium release to improve contractility
- may require higher doses to overcome receptor blockade
- if vasodilatory shock -> norepinephrine
- if cardiogenic shock -> epinephrine
glucagon - using as a vasopressor to bypass beta receptor to activate conversion of ATP to cAMP
- may need to pre-medicate with ondansetron and add PRN regimen due to N/V with glucagon
high dose insulin therapy - increases inotropy and intracellular glucose transport
- goal glucose is 100-250mg/dL
- monitor serum electrolytes and improved contractility
lipid emulsion therapy - limits bioavailability of lipophilic medication by creating a “lipid sink”
- give bolus + infusion
- max dose 10mL/kg
What are the phases of iron toxicity?
- 0.5-2hrs post ingestion: non-specific symptoms like GI upset, abdominal pain, hematemesis, hematochezia
- 6-24 hours post ingestion: latent phase resembling recovery
- 2-24hrs post phase 1: shock stage (acidosis, hypotension, hypovolemia, poor cardiac output)
- 48-96 post ingestion: heptatotoxicity
- Days to weeks after ingestions: GI scarring, obstructions, strictures
What is the general management of iron toxicity?
- get serum iron concentration 4 hours post ingestion
- activated charcoal is NOT effective
- KUB scan
- whole bladder irrigation
- consider deferoxamine for chelation
deferoxamine: iron antidote; chelates iron and enhances renal elimination
- indicated in metabolic acidosis or other signs of shock, clinical deterioration despite IV fluid administration, presence of iron tablets on KUB, serum iron concentration > 500mcg/mL
- start at 15mg/kg/hour
How do we interpret anion and osmolar gap results in alcohol toxicity?
anion gap PLUS osmolar gap:
- methanol toxicity
- ethylene glycol toxicity
- alcoholic ketoacidosis
osmolar gap WITHOUT anion gap:
- isopropyl alcohol toxicity
What is the PK/metabolism of ethylene glycol?
- alcohol dehydrogenase in the liver is the first rate-limiting step in the breakdown of ethylene glycol
- t1/2 is 2.5-4.5 hours
What are the phases of ethylene glycol toxicity?
- 30mins-12 hours post ingestion: CNS effects, N/V, inebriation, lethargy/coma (w/in 4-8 hours), seizures
- 12-24hrs post ingestion: metabolic effects, cardiac compromise, anion gap acidosis
- 2-3 days post ingestion: renal effects, acute tubular necrosis w/in 12-48 hours
What is the PK/metabolism of methanol?
- metabolized by alcohol dehydrogenase to formaldehyde, then to formic acid. This reaction is slow, so there is a delay in toxic metabolite formation
- t1/2 is 14-30hrs, peak levels within 20-90 minutes
What are the phases of methanol toxicity?
- headache, dizziness, ataxia, confusion
- during formic acid accumulation: pronounced visual symptoms, anion gap
How do we manage ethylene glycol and methanol toxicity?
non-pharm:
- gastic lavage and aspiration if pt presents in less than 1 hour
- charcoal is NOT effective
- hemodialysis if EG concentration >100mg/dL or methanol concentration > 45 mg/dL, refractory acidosis, renal failure, or symptomatic
pharm:
- ethanol and fomepizole: inhibits alcohol dehydrogenase to limit metabolism of ethylene glycol
- adjunctive therapy to shunt metabolism towards non toxic metabolites: thiamine, pyridoxine, magnesium, folate
- sodium bicarbonate
- correct hypocalcemia and hypoglycemia
What are the side effects of ethanol therapy for alcohol toxicity? What are the upsides to fomepizole?
Ethanol: phlebitis, AMS, hypoglycemia
Fomepizole: No CNS depression, ICU stay not required
What is the PK/metabolism of isopropyl alcohol?
50-80% metabolized by alcohol dehydrogenase to acetone. Acetone is eliminated via kidneys and lungs.
What are the toxic effects of isopropyl alcohol?
- prolonged CNS depression
- nystagmus or miosis
- ketonemia
- hemorrhagic gastritis
- elevated osmolar gap
- increased serum isopropanol concentrations
- bradycardia/hypotension at high concentrations
How do we treat isopropyl alcohol toxicity?
- gastric lavage
- hydration
- correct electrolyte abnormalities
- hemodialysis if lethal doses, coma, or refractory shock
How is tuberculosis transmitted from one person to another and at what stage of the infection may tuberculosis be transmitted?
Tuberculosis is transmitted by aerosol droplets that are expelled while speaking, coughing, or spitting. Only people with active Tb infections transmit the disease.
What are the differences between active and latent tuberculosis infections? What factors influence if a latent infection becomes active?
Latent:
- has no symptoms
- cannot spread TB bacteria
- usually has a skin test or blood result indicating TB infection
- normal chest x-ray and negative sputum smear
- needs treatment for latent TB infection to prevent active disease
Active:
- symptoms (bad cough, pain in chest, coughing up blood or sputum, weakness or fatigue, weight loss, no appetite, chills, fever, sweating at night)
- may spread TB to others
- usually has skin test or blood result indicating TB infection
- may have abnormal chest x-ray or positive sputum smear or culture
- needs treatment to treat active TB disease
How does the mycobacterial cell wall differ from Gram-neg or Gram-pos cell walls? How does that influence mycobacterial susceptibility to antibiotics?
The mycobacterial cell wall contains mycolic acids and is impermeable to many drugs.
- outer later = mycolic acid rich
- arabinogalactan
- peptidoglycan
- lipid bilayer
What is the activation, MOA, and mechanism of resistance for isoniazid?
Activation - activated by KatG protein
1. KatG activated compound
2. Compound forms adducts with NAD+ and NADP+
3. Active compound inhibits enzymes that use NAD+ and NADP+, like InhA, which are needed for mycolic acid synthesis
MOA - activated isoniazid inhibits InhA, which is a component of FAS II and catalyzes the NADH-dependent reduction of fatty acids bound to an acyl carrier protein. This blocks mycolic acid synthesis and leads to a defective cell wall (bactericidal).
Resistance -
- Downregulation of KatG by the TB
- Over-expression of InhA (target site)
What is the MOA of rifampin?
Activation - none
MOA - bactericidal; most effective when cell division is occurring; binds to RNA polymerase deep within the DNA/RNA channel (allosteric site)
- rifapentine is a derivative of rifampin with a longer half life
What is the MOA and mechanism of resistance for ethambutol?
Activation - none
MOA - bacteriostatic; inhibits mycobacterial arabinosyl transferases that are involved in the polymerization of arabinogalactan. This results in a build up of arabinan and inhibits formation of arabinogalactan and lipoarabinomannan (LAM)
Resistance -
- over-expression of mutations in arabinosyl transferase
What is the activation, MOA, and mechanism of resistance for pyrazinamide?
Activation - converted to pyrazinoic acid by pncA
MOA - active at pH < 5.5; sterilizing agent used against the residual intracellular bacteria, likely due to inhibition of panD (degradation), leading to the inhibition of Coenzyme A synthesis
Resistance -
- mutations in pncA
- mutations in panD
- also RpsA or ClpC1 (unfoldase)
What is the MOA of moxifloxacin?
MOA - bactericidal; traps gyrase on DNA, blocks movement of replication forks, inhibits DNA supercoiling, disrupts DNA replication
What is the MOA and mechanism of resistance for bedaquiline?
MOA - bactericidal; inhibits ATP synthase
Resistance -
- mutations in atpE
What is the activation, MOA, and mechanism of resistance for pretomanid?
Activation - activated by M. tb deazaflavin-dependent nitroreductase (Ddn)
MOA - in aerobic conditions, it forms a reactive intermediate metabolite that inhibits mycolic acid production; in anaerobic conditions, it generates reactive nitrogen species (ROS), causing direct poisoning of the respiratory complex (ATP depletion), thus increasing killing by innate immune system
Why may a drug be second line for tuberculosis? What are our second line agents?
Usually second line because they are less well tolerated & more side effects. Usually only considered if there’s resistance to first line agents, failure of response to 1st line agents, intolerance, or an expert’s opinion.
- streptomycin
- ethionamide
- para-aminosalicylic acid
- cycloserine
- capreomycin
What are the risk factors for infections with M. tuberculosis?
elderly
malnutrition
diabetes
compromised host (chronic renal failure, neoplastic disorders)
alcoholism
IV drug abuse
corticosteroid therapy or other immunosuppressive agents
HIV/AIDS
What is the clinical presentation of tuberculosis in non-HIV infected patients and in HIV-infected patients?
Early - asymptomatic
Late - insidious onset; fever/chills, night sweats, anorexia, weight loss, cough with increasing sputum production, malaise, hemoptysis/SOB
- extrapulmonary tuberculosis presentation depends on the organ system involved
HIV:
- Early HIV: pulmonary tuberculosis is clinically similar to immunocompetent patients; extrapulmonary disease 33%
- Late HIV: diffuse pulmonary involvement (multiple lobes), infrequent cavitation; extrapulmonary disease >70%
*high false-negative rate for TB in HIV patients
How many isolates of M. tuberculosis should have susceptibility testing performed?
ALL isolates should have drug susceptibility performed.
How long should confirmed pulmonary and laryngeal tuberculosis patients be in respiratory/airborne isolation?
They should be in isolation until they are noninfectious while receiving effective therapy, improving clinically, and have negative results for 3 consecutive sputum acid-fast smears collected on different days
What is the prophylaxis for TB in HIV vs. non-HIV infected people? (+ pregnancy and children)
treatment of latent TB infection:
- adult with positive PPD skin test and no other confounding factors: rifampin QD x4 months OR INH + rifapentine weekly x12weeks OR INH + rifampin for 3 months
- HIV pt with positive PPD or TB risk factors: INH for 9 months
What is the treatment of TB in HIV vs. non-HIV infected people?
RIPE:
- Regimen 1- intensive phase with rifampin, isoniazid, pyrazinamide, and ethambutol 7 days/week for 8 weeks; continuation phase with rifampin and INH for 7days/week for 18 weeks OR 5d/week for 18 weeks
- Regimen 2 - intensive phase with rifampin, INH, pyrazinamide, and ethambutol 3x/week for 8 weeks; continuation with rifampin and INH 3x/week for 18 weeks
- Regimen 3 - intensive phase with rifampin, INH, pyrazinamide, and ethambutol 7d/weeks for 2 weeks, then 2x/week for 6 weeks; continuation phase with rifampin and INH 2x/week for 18 weeks
*add vitamin b6 (pyridoxine) 25-50mg daily to patients receiving INH
HIV:
- caution with the 3x/week regimen, since missed doses can lead to treatment failure, relapse, and acquired drug resistance
- do not use the 2x/week regimen
- HIV patients should also receive ART with daily TB meds
- note that rifampin has strong CYP3A4 interactions. Dolutegravir should be increased to BID. Avoid the other protease inhibitors and NNRTIs
How should we treat TB in infants/children and pregnancy?
infants/children: same regimen as adults, may extend to 9 month duration; ethambutol is not recommended for children < 6 yo
pregnancy: avoid streptomycin and pyrazinamide; rifampin, INH, and ethambutol for a minimum of 9 months
What is the 4 month drug-susceptible tuberculosis treatment? When is it not recommended?
rifapentine
moxifloxacin
isoniazid
pyrazinamide
intensive: 7 days/week for 8 weeks
continuation: 7 days/week for 9 weeks
not recommended if:
- <12yo
- weight < 40kg
- pregnant or breastfeeding
- extrapulmonary disease
- prolonged QT syndrome
- receiving more than 1 QT prolonging drug besides moxifloxacin
- drugs interactions
- known or suspected resistance
- pts with HIV who are taking a non-efavirenz based ART
What is the role of directly observed therapy in the treatment of tuberculosis?
Necessary to ensure the patient is taking their TB medications.
What drug interactions and adverse events are associated with each drug utilized in the treatment of tuberculosis? (isoniazid, rifampin, rifabutin, pyrazinamide, ethambutol)
isoniazid -
- AEs: hepatitis, neurotoxicity (pyridoxine excretion)
- drug interactions - CYP450 inhibitor
rifampin -
- AEs: hepatotoxicity (cholestatic), discoloration of body fluids, hypersensitivity reactions
- drug interactions: ultimat CYP450 inducer
rifabutin -
- AEs: orange-colored body fluids, arthralgias, uveitis, leukopenia
- less induction of CYP450s than rifampin
pyrazinamide -
- AEs: hepatotoxicity, hyperuricemia (competes with uric acid for renal elim)
ethambutol - the only one excreted renaly unchanged (adjust for renal dysfunction)
- AEs: peripheral neuropathy, optic neuritis (reversible)
What two organisms (genus + species) cause the vast majority of malaria infections? Which species cause relapse?
plasmodium falciparum
plasmodium vivax
relapse - plasmodium ovale
How do we prevent malaria infections in travelers?
- Insect repellents
- Insecticides
- Bed nets
Chemoprophylaxis: taken before, during, and after travel
- atovaquone-proguanil or doxycyline daily
- chloroquine if the parasites are susceptible
- mefoquine weekly (for long trips)
- primaquine if >90% P. vivax in the area
How does the Plasmodium species metabolize hemoglobin? How do aminoquinolines (quinine and cloroquine) result in the buildup of toxic heme within malaria parasite-infected cells?
The parasite ingests hemoglobin and degrades it to amino acids and free heme in the food vacuole. However, the free heme is toxic. The parasite polymerizes heme into hemozoin (salt crystal) which is nontoxic.
Chloroquine accumulates in the food vacuole and inhibits heme polymerization, thus causing the buildup of toxic heme.
What is the MOA of these anti-malarial drugs: artemisinin, malarone (atovaquone + proguanil), chloroquine, quinine, primaquine, doxycyline
artemisinin - blood schizonticide; after activation (likely from heme-iron), it forms free radicals and targets parasite proteins and lipids. It also may inhibit PfPI3K.
- very short half life though (1-2 hours)
- often paired with a longer half life drug
malarone - proguanil + atovaquone; kills liver and blood stages (not hypnozoites)
- atovaquone: selective inhibitor (ubiquinone analog) of malaria mitochondrial cytochrome bc1 complex, which inhibits electron transport, resulting in collapse of the mitochonrial membrane
- proguanil: selective inhibitor of plasmodial DHFR-TS, which is crucial for parasite purine and pyrimidine synthesis; also has inherent antimalarial activity (synergistic with atovaquone)
chloroquine - blood schizonticide; interferes with heme polymerization, causing a buildup of toxic heme in the infected cells food vacuole
- resistance is problem
quinine - blood schizonticide; similar to chloroquine MOA
primaquine - tissue schizonticide; after activation, it produces H2O2, which kills plasmodium parasites; drug of choice for liver stages (actively growing and hypnozoites) of P. vivax and P. ovale in combination with chloroquine
doxycyline - targets components of the apicoplast (needed for many essential biochemical processes)
What is the key functional group in artemisinin?
endoperoxide
How is primaquine activated?
- hydroxylation by CYP2D6 in humans to the active form.
- if there’s a CYP2D6 mutation, there may be resistance - spontaneous oxidation to quinoneimines, which produces H2O2. Reduction by NADPH creates a catalytic cycle of H2O2 production. This H2O2 kills plasmodium parasites.
What are the adverse effects that can occur with chloroquine, quinine, and primaquine? What about mefloquine?
Quinine:
- Cinchonism - tinnitis, headache, nausea, dizziness, flushing, & visual disturbances
- Can stimulate uterine contractions
- Hemolysis if G6PD deficiency present
- Also metabolized by CYP3A4, so drug interactions are a problem
Mefloquine: psyche effects, sleep disturbances
Which antimalarial drugs are effective against the hyponozoite stage of P. vivax?
Primaquine (in combination with chloroquine)
What are the symptoms of giardiasis and amebiasis?
giardiasis - diarrheal disease that can range from asymptomatic to severe diarrhea & malabsorption
amebiasis - most are asymptomatic, some include diarrhea, increased flatulence, and/or abdominal cramps
What drugs are used for treatment of toxoplasmosis, pneumocystis, giardiasis, amebiasis, and trichomoniasis?
toxoplasmosis - pyrimethamine (+ leucovorin) + sulfadiazine
pneumocystis - trimethoprim-sulfamethoxazole
giardiasis - metronidazole or nitazoxanide
amebiasis - metronidazole
trichomoniasis - metronidazole
What is cysticercosis and neurocysticercosis?
cysticercosis - caused by eating eggs produced by Taenia solium (pork tapeworm). It produces cysticerci in the brain (causing seizures, headache, and vomiting) and in the eyes.
neurocysticercosis - serious disease in the brain from cysticercosis
What parasite is amphotericin B used for?
Amphotericin B used for leishmaniasis
What is the spectrum, MOA, and basis for specificity for albendazole and mebendazole?
benzimidazoles - bind to tubulin to inhibit the formation of microtubules (cap microtubules)
- have higher affinity to the helminth tubulin (worms)
mebendazole - used for pinworms, hookworms, ascariasis, and trichuriasis
- do not use in 1st trimester
albendazole - drug of choice for cysticercosis
- also for pinworms, hookworms, ascariasis, and trichuriasis
- do not use in pregnant women
What is the spectrum, MOA, and basis for specificity for ivermectin?
Spectrum - drug of choice for strongyloidiasis and onchocerciasis
MOA - paralyzes microfilariae by binding to GABA and glutamate-activated Cl- channels that are found in nematode nerve or muscle cells. It causes hyperpolarization by increasing intracellular chloride concentration (but it doesn’t kill adult worms, it only blocks the release of progeny).
What is the spectrum, MOA, and basis for specificity for metronidazole?
Spectrum - drug of choice for extraintestinal Entamoeba histolytica, giardiasis, and trichomoniasis
MOA - anaerobes selectively activate metronidazole, which produced free radicals that damage DNA
(Tinidazole is a similar drug with less toxicity)
What is the spectrum, MOA, and basis for specificity for nifurtimox?
Spectrum - most commonly used for T. cruzi
MOA - activated by NADH-dependent mitrochondrial nitroreductase to generate nitro radical anions
What is the spectrum, MOA, and basis for specificity for nitazoxanide?
Spectrum - drug of choice for cryptosporidium, also inhibits growth of trophozoites of giardia lamblia
MOA - after activation, it disrupts the energy cycle of anaerobes. It’s a noncompetitive inhibitor of PFOR, so it inhibits anaerobic metabolism
What is the spectrum, MOA, and basis for specificity for praziquantel?
Spectrum - drug of choice for all schistosomiasis (blood fukes)
MOA - binds to helminth transient receptor potential ion channel (TRPM), which causes a Ca2+ influx and paralyses the worm so it detaches from the blood vessel wall.
What is the spectrum, MOA, and basis for specificity for pyrantel pamoate?
Spectrum - broad-spectrum; highly effective for pinworms and ascaris, moderately effective against hookworms
MOA - depolarizing neuromuscular blocking agent that causes release of acetylcholine and inhibition of cholinesterase. This causes the worms to be paralyzed and expelled.
What are the goals of immunosuppressive therapy?
to promote acceptance of the donor allograft, prolonging patient and graft survival & to prevent rejection while minimizing the risks of infection, toxicity, and malignancy.
Under-immunosuppression -> rejection
Over-immunosuppression -> infection, toxicity, malignancy
What are the different immunosuppression regimens for induction?
polyclonal antibodies - rabbit antithymocyte globulin (Thymoglobulin) & horse antithymocyte globulin (ATGAM)
- used for induction or rejection
- anti-CD3 polyclonal antibody
- causes lymphocyte depletion (reduces T-lymphocytes)
monoclonal antibodies - alemtuzumab (Campath-1H)
- only for kidney transplant
- anti-CD52 monoclonal antibody
- causes profound depletion of T cells (antibody-dependent cellular cytotoxicity)
IL-2⍺ receptor antagonists - basiliximab
- binds the ⍺ subunit of IL-2R to completely inhibit IL-2 mediated activation of lymphocytes
- monoclonal
- non-lymphodepleting
What is the dosing, adverse effects, and monitoring for Thymoglobulin and ATGAM
Thymoglobulin: 1-1.5 mg/kg/day IV
ATGAM: 10-15 mg/kg/day IV
Adverse effects:
- Leukopenia, thrombocytopenia (dose limiting)
- Fever, chills (pre-medicate with diphenhydramine and acetaminophen)
Monitoring:
- WBC, absolute lymphocyte count (ALC), platelets
- vital signs
What is the dosing, adverse effects, and monitoring for alemtuzumab?
Alemtuzumab (Campath-1H): 30 mg IVPB x 1 dose intraoperatively
Adverse effects:
- infusion-related (chills, rigors, fever) [pre-medicate with diphenhydramine and APAP]
Monitoring:
- WBC, ALC, platelets
- Vital signs
What is the dosing for basiliximab?
20mg IVPB intraoperatively and post-op day 4
- no pre-medications needed
How do we choose an induction agent?
- lymphocyte depleting therapy (Thymoglobulin [alemtuzumab as well]) more commonly used–especially for patient with high immunologic risk
Basiliximab is used for patients with:
- history of malignancy
- high infection risk, immunocompromised
- HIV or untreated HCV
- over 65 years old (since their immune system has likely weaned over time)
What are the different immunosuppression regimens for maintenance?
The normal regimen is a triple drug regimen with:
- calcineurin inhibitor (tacrolimus)
- antimetabolite (mycophenolate)
- +/- corticosteroid (prednisone)
Another approach is to avoid/minimize the CNI to improve renal function:
- sirolimus + mycophenolate or azathioprine + corticosteroids
- everolimus + low-dose tacrolimus + corticosteroids
- belatacaept + mycophenolate + corticosteroids
Another approach is corticosteroid withdrawal or avoidance to decrease long-term associated toxicity
What are the calcineurin inhibitors? What is their MOA, dosing pearls, formulation differences, adverse effects, and monitoring parameters?
MOA: induces immunosuppression by inhibiting signal-1 of T-cell activation & inhibits calcineurin phosphatase enzyme within the T cell, which prevents subsequent T-cell activation
Cyclosporin: (Neoral, Gengraft, Sandimmune); do not use non-modified (Sandimmune)
- target 12hr trough 100-400 ng/mL
- CYP3A4 and pgp substrate, inhibitors increase exposure
- elimination is highly variable
- AEs: hypertension, hypercholesterolemia, hypertriglyceridemia, gingival hyperplasia, hirsutism
Tacrolimus: (Prograf, Astagraf XL [do not use], Envarsus XR); immediate release (Prograf) is BID, ER is QD and has less toxicity
- there are different conversions for IR vs. ER dosing (not 1:!)
- goal 12-hr trough is 5-15 ng/mL
- CYP3A4 and pgp substrate, inhibitors increase exposure
- AEs: neurotoxicity, hyperglycemia, alopecia
How does liver or renal dysfunction impact CNI PK?
Liver dysfunction: causes alterations
- tacrolimus is primarily eliminated by hepatic metabolism, so the t1/2 is prolonged in liver dysfunction
Renal dysfunction: does not cause alterations
- dose adjustments NOT necessary
What drugs are known to induce CYP450? What drugs are known to inhibit CYP450?
Induce:
- phenytoin
- carbamazepine
- phenobarbital
- rifampin
Inhibit:
- erythromycin, clarithromycin
- azoles
- diltiazem, verapamil
- ritonavir
- grapefruit juice
What are the antimetabolites? What is their MOA, dosing pearls, formulation differences, adverse effects, and monitoring parameters?
azathioprine (Imuran): AZA is converted to 6-MP in the blood which incorporates into nucleic acids and eventually inhibits RNA/DNA synthesis, thus inhibiting immune cell proliferation
- AEs: places with high cell turnover; GI (abdominal pain, N/V, diarrhea, dyspepsia), bone marrow suppression (agranulocytosis, macrocytic anemia, leukopenia, neutropenia, thrombocytopenia)
- when given with allopurinol or febuxostat, you need to reduce AZA dose by 50-75%
Mycophenolic acid: (mycophenolate mofetil [CellCept] & mycophenolate sodium [Myfortic])inhibits de novo pathway of purine synthesis, which limits the progression of activated T and B cells.
- mofetil and sodium formulations are equivalent and interchangeable, but require a dosing conversion; MMF 250mg = MPS 180mg; IV:PO is 1:1
- AEs: FDA pregnancy category D (teratogenic) [REMS program]
- drug interactions: other myelosuppressive drugs, like valganciclovir, sirolimus, etc.
What are the mTOR inhibitors? What is their MOA, dosing pearls, formulation differences, adverse effects, and monitoring parameters?
mTOR inhibitors: (sirolimus, everolimus) these bind to FKBP12, which fuses with mTOR to inhibit T-cell proliferation
- metabolized by CYP3A4 and pgp, inhibitors increase dose/toxicities
- sirolimus is approved for kidney transplant rejection prophylaxis
- everolimus is approved for kidney & liver transplant rejection prophylaxis
- AEs: edema, hyperlipidemia, hypertriglyceridemia, impaired wound healing, mouth ulcers, proteinuria
- these cannot be used immediately post-transplant due to imparied wound healing
What are the corticosteroids we use in SOT? What is their MOA and adverse effects?
methylprednisolone, prednisone, dexamethasone: inhibit cytokine production by T cells and macrophages, interferes with cell migration, recognition, etc.
- AEs: related to average dose and cumulative duration of use; hyperglycemia, hypertension, impaired wound healing, etc.
What is the T-cell co-stimulation blocker? What is its MOA, dosing pearls, formulation differences, adverse effects, and monitoring parameters?
T-cell co-stimulation blocker (belatacept): blocks signal-2 of T-cell activation and the CD28 mediated co-stimulation of T-lymphocytes, thus inhibiting T lymphocyte proliferation and cytokine production
- relative contraindication for use in liver transplant
- only dosed IV, given q4 weeks at an infusion clinic
- used as a replacement or adjunct to CNI
- due to post-transplant lymphoproliferative disorder, contraindicated in EBC seronegative patients
How do we treat cellular rejection vs. antibody mediated rejection?
Acute cellular rejection (ACR):
- mild-moderate: high-dose corticosteroids (methylprednisolone 250-1000mg IV for 3-5 days)
- mod-severe or steroid-resistant: T-lymphocyte depleting therapy (rabbit antithymocyte globulin 1.5mg/kg/day IV for 6-7 days; alemtuzumab if refractory)
Antibody mediated rejection (AMR):
- steroids +/- rituximab +/- IVIG
- rituximab - anti CD20 chimeric monoclonal antibody; need to watch closely for infusion reaction complex that can occur w/in 24 hours of the infusion [ARDS, V fib, shock]
- IVIG - use sucrose formulations (Gammagard, Gamunex)
What is the prophylaxis for relevant opportunistic infections in SOT?
- Pneumocystis carinii or pneumocystis jirovecii -> bactrim
- cytomegalovirus -> valganciclovir
- fungal infections -> posaconazole
