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Glossary of Lab Medicine Final UCSD SSPPS

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What is apotransferrin versus ferritin versus transferrin?
Apotranferrrin is a plasma iron binding protein with no iron bound. Ferritin is serum protein used to determine iron status, and the chief storage form of iron. Transferrin is the same as apotransferrin, except it has iron bound. Ferritin is the most sensitive indicator of low iron.
what is hemoglobin S disease versus hemoglobin S trait?
The diease is homozygosity for the sickle hemoglobin beta chain, while the trait is heterozygosity. The hemoglobin trait yields no clinical or hematological manifestations.
What is fetal hemoglobin, hemoglobin A2, and adult hemoglobin?
Fetal is two alpha chains and two gamma chains. A2 is two alpha chains and two delta chains. Adult is two alpha chains and two beta chains
How many genes does each person have for the hemoglobin alpha chains, and what are the alpha thalassemias?
Each person normally has two alpha genes on each of their chromosome 16s, so 4. If missing one or two, they have a silent (no clinical manifestation) alpha thalassemia. If they are missing 3, they have hemoglobin H disease. If they are missing 4, it is known as Bart’s disease, and is fatal before or immediately after birth.
What is B12 for, and how to detect deficiency?
Cofactor for synthesis of folate, and can be measured directly or by methylmalonic acid levels since B12 is also a cofactor for its conversion to succinate. B12 is stored in the liver and normal stores can last many months (folate runs out in just weeks if intake stops)
Causes of macrocytic anemia, and how it affects Hct, Hgb, MCV, RBC?
B12 (pernicious) or folate deficiency. Decreases Hct, Hgb, RBC, and increases MCV. If pernicious anemia, schilling test will be positive and B12 will be low. If folate deficiency, folate will be low.
Acute blood loss will cause what type of anemia, and how will it affect Hct, Hgb, Ret ct, and RBCs?
Normocytic anemia (which can also be caused by hemolytic (autoimmune or non), and anemia of chronic disease). Hct, Hgb, Ret ct, and RBCs will all be decreased with blood loss, which is true of the other normocytic anemias as well (except for hemolytic anemia which has increased Ret ct). Incidentally, Bilirubin also increases in hemolytic anemia.
What happens to haptoglobin in hemolytic anemia?
It decreases due to the increased binding and clearance of free heme.
What is the coombs test used for?
To detect autoimmune anemia (a normocytic anemia)
What causes microcytic anemia?
Iron deficiency. It also leads to decrease in Hct, Hgb, MCV, Fe, Fe Sat, Ferritin, but increase in TIBC
How to test for thalassemias?
HPLC (High Performance Liquid Chromatography)
How does the sickle cell trait affect RBC, Hgb, Hct, MCV, MCH?
No effect
What causes hemolytic anemia?
Can be autoimmune (antibodies against RBCs), or a variety of things including drugs like quinine, quinidine, fluoroquinolones (such as levofloxacin or cipro)
What Hgb level is considered anemia, and at what Hbg level should transfusion be considered?
<10 is anemia, and if <7, transfusion should be considered
The incidence of iron-deficiency anemia?
9% in toddlers, 2% in men, 11% in menstruating females, and nearly 50% in pregnancy.
Cause of iron deficiency anemia?
Usually dietary in children, and blood loss in adults
What is hemosiderosis?
One of the three main types of iron overload. This type is without tissue damage. The other types are hemochromatosis (associated with tissue injury) and hereditary hemochromatosis (the classic disorder)
What is hemochromatosis?
One of the three types of iron overload. It is associated with tissue injury, and usually caused by chronic, excessive absorption of iron. The other types of iron overload are hemosiderosis (non-tissue injury) and hereditary hemochromatosis (the classic iron overload case).
What is hereditary hemochromatosis?
One of the three types of iron overload. It is the classic disorder of iron overload, and homozygosity is about 5 per 1000.
What condition comes to mind if iron saturation is greater than 60%?
Iron overload (hemosiderosis, hemochromatosis, or hereditary hemochromatosis). Typical saturation is 20-50% in males and 15-50% in females. All the iron in the serum is bound to transferrin, and unbound transferrin is called apotransferrin. %sat = Iron/TIBC
What is the effect on serum iron, iron saturation of transferrin, ferritin, transferrin, and TIBC in a state of iron overload?
All three types of iron overload cause serum iron, iron saturation of transferrin, and ferritin to be high. However, in hemochromatosis, transferrin and TIBC are decreased
Definition of serum iron?
Fe(III) bound to tansferrin (and other serum proteins), but does not include iron in RBCs or iron bound to free Hgb
Causes of low serum iron?
Iron deficiency, chronic inflammatory disorders, hemorrhage, blood donation, menstruation. And also during early treatment for anemia such as B12 injections in which the sudden increase in hemoglobin synthesis draws iron from serum and iron stores.
effect of BCPs on serum iron?
Oral contraceptives increase transferrin production, so increases serum iron. Other things that increase serum iron are iron overload, acute iron poisoning, ingestion of iron medication, parenteral iron administration, and hepatitis (release of iron from liver iron stores).
Definition of TIBC?
Measurement of the maximum amount of iron that serum proteins (mostly transferrin) can bind. If iron levels approach TIBC such as in iron overload, there is a risk of “spill-over” of transferrin’s binding capacity, and free iron causing toxicity.
How is TIBC affected in iron deficiency, inflammation, malignancy, and malnutrition?
TIBC is increased in iron deficiency (less transferrin occupied by iron), but decreased in acute and chronic inflammation, malignancy, and malnutrition.
How do transferrin levels change in acute versus chronic inflammation?
Both cause decreased transferrin, but for different reasons. Acute inflammation causes decrease because transferrin is one of the negative acute phase reactants. In chronic inflammation, there is simply less transferrin synthesis
What is another name for the apotransferrin level?
UIBC (unsaturated iron binding capacity)
How is iron stored in ferritin, and what are the weird things about ferritin levels?
Serum ferritin is very low (about 1%). Most ferritin is in tissues, where iron is stored as micelles of hydrated ferric oxide-phosphate complexes adhering to the inner surface. Ferritin is a good indicator of iron status except in inflammatory conditions like RA, renal disease, malignancies, viral hepatitis, and iron storage diseases, in which ferritin is high but iron is low.
What is the gold standard for testing iron status?
Cytochemical staining using the Prussian Blue reaction on hemosiderin from bone marrow aspirates
How can measurement of iron in liver biopsies be helpful?
Can help diagnose hemochromatosis in cases when serum iron and TIBC may be borderline
What kind of hemotologic problem can levofloxacin cause?
Autoimmune, drug-induced hemolytic anemia. Other fluoroquinolones, quinine, and quinidine can also do this. Usually Cipro does this more than Levaquin
How to calculate % iron binding saturation?
Iron/TIBC (x100)
Three classes of drugs that can cause iron deficiency?
Antacids (interfere with iron absorption by binding and by increasing the pH), NSAIDS (GI bleed), and steroids
What is aplastic anemia?
Diverse group of bone marrow disorders characterized by pancytopenia (reduced RBC, WBCs, platelets) due to reduction of hematopoietic marrow stem cells (often drug-induced, and less likely to recover. In hypoplastic anemia, recovery after drug is stopped is common.
Normal ratio of lymphocytes in the blood?
T:B is 4:1. Viral infections increase number of lymphocytes, and leukemias can increase all types of blood cells
What is a basophil?
Leukocyte with pale-staining nucleus with usually two lobes and prominent blue granules containing vasoactive amines such as histamine and serotonin, which increase vascular permeability and secretions. Basophils and eosinophils increase with allergic response. Basophils are related to mast cells and have receptors for IgE.
What are eosinophils?
Leukocyte with red-stained granules containing eosinophil basic protein, which is toxic to pericytes (do not contain histamine). The nucleus has two lobes, and increase in allergy with basophils, and also have IgE receptors
What is coagulation versus hemostasis?
Coagulation is the enzyme cascade leading to a clot, and hemostasis is the process of stopping bleeding (I don’t know if their meanings overlap or are exclusive)
What is hypoplastic anemia?
The form of anemia due to varying degrees of erythocytic hypoplasia
What is leukemia versus lymphoma?
Leukemia is malignancy of the blood-forming organs, characterized by distorted proliferation of leukocytes and their precursors (too many immature cells). WBCs can either increase or decrease. Lymphoma is malignancy of lymphocytes, causing large lymph nodes and spleen. However, there is overlap between the two diseases
What is leukopenia?
Decrease in number of leukocytes in the blood (<5000/ml). Lymphopenia is low number of lymphocytes
What is a monocyte?
Mononuclear phagocytic leukocyte (an APC), which is the precursor to a macrophage (also an APC)
What is a neutrophil?
Polymorphonuclear leukocyte, or segmented leukocyte. It is a granular leukocyte with a nucleus of 3-5 lobes. It can do chemotaxis, adhere to immune complexes, and phagocytose bacteria coated with Ab. They increase in number in bacterial infections, are the most common leukocyte, have complement receptors, Fc antibody receptors, and toll receptors (such as for n-methionine). They kill using lysosomes.
What are the nongranular leukocytes?
Lymphocytes and monocytes
What are reticulocytes?
Young RBCs showing basophilic reticulum (rough ER on which hemoglobin is synthesized). Increased in hemolytic anemia, but decreased in blood loss.
What are thrombocytes?
Platelets. They increase in inflammation, disseminated cancer, thrombocytopenic purpura (TTP), bone marrow failure, and in disseminated intravascular coagulation (DIC)
What is thrombocytopenia, and what causes it?
A reduction in the number of platelets. Over half are caused by drugs, and of the drug-induced ones, half are caused by quinine, quinidine, rifampine, heparin, and sulfonamides (including Celebrex)
What is von Willebrands disease?
Autosomal dominant hemorrhagic disease caused by a lack of von Willebrand factor (vWF) and low coagulation factor VIII which is carried on vWF. There are also other diseases involving vWF that make clotting happen too well due to variations in vWF.
What role does vWF play in the clotting cascade?
In tissue injury, vWF sticks to subendothelial matrix (collagen), and binds to GPIb-IX-V, and the V (in GPIb-IX-V) is made by platelets, so it helps platelets stick to collagen via vWF. However, the sticking of platelets is redundant because GPIa-IIa from platelets also sticks to collagen.
How do platelets stick to each other in forming a platelet plug?
Each platelet sticks to fibrinogen (factor I) via IIb-IIIa
What do activated platelets secrete?
ADP and thromboxane (which causes vasoconstriction). They also synthesize and display factor Va on their surfaces. The key is that Va complexes with Xa to convert prothrombin (II) to thrombin (IIa), which then converts fobrinogen (I) into fibrin (Ia)
What is the significance of platelet-activated synthesis of factor V?
Factor Va, displayed on the surface binds to Xa, which then converts prothrombin (II) to thrombin (IIa), which then converts fibrinogen (I) to fibrin (Ia). XIII then crosslinks fibrin to make a stable clot
What does factor XIII do?
Crosslinks fibrin to make a stable clot.
Where does the Xa come from that forms the complex with Va on the surface of activated platelets?
When endothelium is damaged, it releases tissue factor (TF), which activates VII to VIIa, which then activated X to Xa. This is the extrinsic pathway measured by PT, and helps form the fibrin clot
Which part of the clotting cascade is considered the extrinsic versus the intrinsic pathway, and which corresponds to the PT time versus the PTT time, and which is the heparin-sensitive system versus the factor VII dependent system?
The extrinsic system is TF→VII to VIIa→X to Xa→VaXa→II to IIa→I to Ia, and is measured using PT time to evaluate this factor VII dependent pathway (relies on vit-K). The intrinsic pathway is neg. charged collagen→XII to XIIa→XI to XIa→IX to IXa, which complexes with VIIIa to convert X into Xa→XaVa→II to IIa→I to Ia, and is measured using PTT, good for monitoring heparin which mainly inhibits II, but also X, XI, and XII because IIa amplifies these
How does the intrinsic clotting cascade work?
Starts with exposed negatively charged collagen in a damaged blood vessel, which activates XII to XIIa. XIIa then activates XI to XIa, which then activates IX to IXa. IXa then complexes with VIIIa (which is stuck to vWF) to activate more X into Xa. The PTT is used to evaluate this system.
What does IIa activate?
IIa is thrombin, and works to amplify the clotting system. It activates more VIIIa (the one that complexes with IXa to activate X into Xa) as well as Va (on platelet surface) and XIa (feedback into the cascade to activate more X).
How to form a platelet plug?
There are three main reactions to make a plug: (1) Adhering of platelets to damaged cells via GPIb-IX-V binding to vWF, (2) Platelets adhering to each other via IIb-IIIa connections to fibrinogen (factor I), and (3) platelets adhering to collagen through GPIa-IIa. These activated platelets secrete ADP and thromboxane, and display Va on their surface.
How to form a fibrin clot?
The extrinsic system (TF down to Xa complexing with Va)
What is unique about factors V and VIII?
They are at the clot site (V on surface of activated platelets stuck to subendothelial matrix, and VIII carried by vWF, stuck to the collagen exposed only upon injury), so they limit clotting activity to the site of injury.
Describe PT (prothrombin time)?
Usually about 10s, it is the time for the conversion of prothrombin to thrombin. It evaluates the factor VII dependent pathways (coumadin-sensitive, due to its inhibition of VII synthesis, as well as X, IX, and II). It is done by adding TF to plasma. (TF + platelet phospholipids + Va)→ VIIa→ XaVa→ IIa→ Ia (clot). It is often converted into INR which is (patient PT/control PT)^ISI, where ISI is the international sensitivity index, and is essentially 1.0. Normal INR is 0.9-1.5, but should be 2-3 for coumadin patients needing basic blood-thinning, and even higher for high risk clot patients). INR can be directly compared between labs, but PT cannot. It is best d
Describe PTT (partial thromboplastin time)?
Normally 23 to 33.5seconds, it is the time to form a clot, and evaluates the factor XII-dependent pathway (intrinsic). It is done by exposing blood to negatively charged surface (to mimic collagen), and is best for monitoring heparin due to inhibition of factor II, which is responsible for amplifying X, XI, and XII.
What does heparin do to the clotting cascade?
Its activity requires antithrombin (factor III), also known as ATIII. ATIII inhibits IIa (thrombin), IXa and Xa. Heparin is commonly used for venous thrombosis, pulmonary embolism, initial stabilization of angina and MI, coronary angioplasty, and cardiac bypass surgery
What does warfarin do in the clotting cascade?
Antagonizes vitK, which is necessary for the carboxylation (activation) of factors II, VII, IX, and X. However, it has no effect on circulating (already synthesized) factors, so onset of action is slow (half life of clotting elements is 4-5 days, and need <50% clotting factors before coumadin effects will show up)
Mneumonic for remembering the intrinsic coagulation pathway?
TENET: Twelve (which is activated by collagen), activates Eleven, which activates Nine, which combines with Eight, to activate Ten.
How does Streptokinase work?
It is a thrombolytic drug (like t-PA), which non-covalently binds to plasminogen, activating it to form free plasmin, which then digests fibrin clots
How does t-PA work? Reteplase?
Tissue Plasminogen Activator is a thrombolytic like streptokinase. It works by activating plasminogen bound to fibrin to digest the clot. Retaplase is a deletion mutant of t-PA.
How does aspirin work as an antiplatelet?
Acetylates serin residues on COX to prevent formation of thomboxane A2 which normally causes vasocronstriction and platelet aggregation. It is irreversible, and the half-life of a platelet is 5-7 days.
How does Clopidogrel work?
(Plavix). Antiplatelet, blocks aggregation by blocking the purine receptor. It may cause thrombotic thrombocytopenic purpura (TTP)
How does abciximab work?
(Reopro). Fab fragment of humanized monoclonal antibody directed against the IIb/IIIa receptor (so no fibrinogen binding platelets together.
What is the effect of steroids on neutrophils and lymphocytes?
Increases neutrophils (that’s weird because neutrophils increase with inflammation, but steroids are anti-inflammatory). However, steroids decrease lymphocytes, explaining their immunosuppressive activity
How to differentiate between drug-induced and stem-cell problem causing neutropenia, lymphopenia, and thrombocytopenia?
Can stop the drug. But also, if one cell line is decreased, it is usually drug-induced, versus if all cells are decreased, it might indicate a stem cell problem (which can be a disease or still drug-induced)
What effect can blood lipids have on INR, PT, PTT?
Probably little effect on PTT (the intrinsic pathway), but if blood lipids go down too much, vit K absorption and mobilization could be compromised, which could inhibit the factor-VII-dependent (extrinsic pathway) and so increase INR and PT. INR= (PTpt/PTcontrol)^ISI. Coumadin patients should be on a steady (not up and down) diet of green leafy vegetables so vit K won’t affect clotting too much
What types of specimens should be provided to the lab for an overdosed patient?
Blood or serum, depending on the analyte, especially if drug effects are correlated with concentration; Urine is good for drugs that are extensively metabolized or cleared (common for illegal drugs), or blood concentration is too low; gastric fluid from lavage or emesis is best to determine parent drug of overdose; pills, capsules, powders found with the patient.
What is protocol for treatment of overdose patient?
If comatose, ABCD (airway, breathing, circulation, drugs), then supportive care (emesis, lavage, IV fluids, charcoal, cathartics, pressorss, cardiac monitoring), then antidote if available/indicated, and rarely peritoneal dialysis, hemodialysis, or hemoperfusion
When do zero-order kinetics apply to toxicology?
For drugs like ethanol which are always eliminated by zero-order, or for other drugs which become zero-order when enzymes are saturated from overdose, and secondary metabolic routes produce toxic metabolites. Half-lives don’t apply to zero-order kinetics
When is steady-state reached in administration of drugs?
After about 4 half-lives (94% of steady-state)
Common drug class that induces liver enzymes?
Barbiturates
Common drug classs that inhibits (competes for) liver enzymes?
Coumarins, cimetidine
What drug can be used to treat alcoholism?
Disulfiram (antabuse), because it inhibits ALDH (aldehyde dehydrogenase), so acetylaldehyde builds up, causing flushing, N/V, etc..
Three metabolic pathways for EtOH?
ALDH in cytosol, microsomal ethanol oxidation (inducible), and peroxidase-catalase (minor)
What toxin is a common cause of hyperosmolarity in the ER?
EtOH. Affects cognition and cortical functions first, then lower level functions like breathing at very high levels
Rate of metabolism of EtOH?
0.01 to 0.02% w/v/hr, but can be increased to 0.03%
Symptoms of methanol toxicity?
Profound metabolic acidosis. It uncouples oxidative phosphorylation and is metabolized to formic acid. Its metabolites can cause blindness. As little as 30ml can be fatal
How to treat methanol poisoning?
Ethanol drip until 100-150mg/dL (competitively inhibits ADH, so can’t make formaldehyde or formate). Methanol can be removed by dialysis (if >50mg/dL). Can also give 4-methylpyrazole to inhibit ADH. Hemodialysis is also an option
What type of drug screens are there?
IA (immunological assay) which is quick, sensitive, specific, cheap, and automated, but you have to know what you’re looking for. The other is TLC (think layer chromatography). It works by molecular weight determining how far it travels. It has broad spectrum, but it’s slow, comlicated, and not sensitive.
Key difference between zero and 1st order kinetics?
Zero order is a constant amount cleared per unit time, 1st order is constant percent cleared per unit time
Main effect(s) of Isopropanol toxicology?
Has twice the CNS depressant effect as equivalent dose of EtOH. Causes upper GI bleed (from acetone).
Isopropanol is metabolized to what?
Acetone (using ADH). Belching helps to eliminate the toxin
CNS effects of ethylene glycol?
Same depressant effects as EtOH, but has toxic metabolites (glycolic acid and oxalic acid)
How to detect ethylene glycol toxicity?
Osmol gap and hypocalcemia (oxalic acid + calcium = deposition)
Effects of ethylene glycol metabolites?
Glycolic acid and oxalic acid causes myocardial depression and renal necrosis (necrosis due to calcium deposition from oxalic acid + calcium reaction)
Three stages of ethylene glycol intoxication?
(1) CNS depression, 1-12 hrs, (2) cardiotoxic, 12-24 hrs, (3) renal stage, 24-72 hrs.
How to treat ethylene glycol intoxication?
Ethanol to inhibit formation of toxic metabolites (competing for ADH), bicarb for metabolic acidosis, Ca replacement if necessary, and/or 4-methylpyrazole to inhibit ADH. Hemodialysis can also be used.
What is methylpyrazole used for?
Inhibits ADH to treat methanol or ethylene glycol poisoning
How does salicylate poisoning lead to acidosis?
Combination of two ways: (1) stimulates medulla→ hyperthermia/resp alkalosis→ renal bicarb excretion→ respiratory depression→ acidosis. (2) salicylates and other organic acids cause a direct metabolic acidosis, especially if renal impairment. Uncoupling of oxidative phosphorylation leads to increased organic acids
Common sxs of salicylate poisoning?
Tinnitis, hyperthermia, hyperventilation, CNS disturbances.
How to treat salicylate poisoning?
Hydration, glucose, K+ supplements, bicarb, hemodialysis
What concentration of APAP is hepatotoxic?
>200mcg/mL (at 4 hours). Highest levels occur 4 hours post ingestion
What does the measured half life of APAP indicate?
Normal half life is 2-3 hrs. If >4 hrs, it indicates hepatotoxicity. If >12hrs, hepatic coma is likely
Acute dose of APAP that is toxic?
For adults, 150-250mg/kg. Children under 10 are more resistant to APAP toxicity.
Why is APAP hepatotoxic?
It is metabolized by glucuronidation and sulfation, with a small amount going to imidoquinone (a toxic intermediate). Imidoquinone must be inactivated by reduced glutathione, which in overdose, gets depleted, leaving imidoquinone to damage hepatocytes. N-acetylcysteine (Mucomyst) can help replenish glutathione
How does N-acetylcysteine work?
(Mucomyst) helps prevent APAP toxicity by replenishing glutathione which is necessary for metabolizing the toxic intermediate imidoquinone.
What are the stages of APAP toxicity?
GI distress (0-8 hrs), general well being (0-24 hrs), liver toxicity (8-36 hrs) which is fulminant liver failure if large overdose, recovery (days to weeks) in which LFTs return to normal in 5-7 days and complete resolution takes weeks
How to treat APAP overdose?
Activated charcoal (if catch it early enough), N-acetylcysteine (if given early enough can completely prevent liver damage)
Indication for N-acetylcysteine?
APAP concentrations above the nomogram line, or elevated AST, prolonged serum APAP levels, and hx suggestive of chronic APAP overdose.
How to measure tricyclic antidepressant levels in overdose?
Monitor by EKG, which is better than blood levels because blood levels don’t correlate well with effects.
Sxs of tricyclic antidepressant overdose?
Long QTc, wide QRS, arrhythmias. The uscarinic blockade, NE reuptake block, alpha adrenergic block, and membrane stabilization can lead to arrhythmia and cardiac arrest. Use of SSRIs has made this toxicity less common. No good treatment for TCA overdose
Presentation of BDZ toxicity?
Sedative/hypnotic, but rarealy coma unless taken with other other CNS depressants like ethanol. Antidote is flumezanil (competitive antagonist), but is rarely used due to lack of overt toxicity of BDZs.
Flumazenil used for?
BDZ overdose (competitive antagonist), but rarely used due to lack of overt toxicity of BDZs. It is contraindicated if patient took tricyclcic antidepressants due to potential precipitation of seizures
Sx triad of opiate toxicity?
Pinpoint pupils, coma, respiratory depression.
How to treat opiate toxicity?
Naloxone, a competitive antagonist. Should be given 0.4-2mg IV every 2-3 minutes until improvement (up to 10mg). If no improvement, consider alternate diagnosis. Naloxone has shorter half life than most opiates, so patient needs to be monitored for 24-48hrs
How does cocaine cause toxicity? (based on two main mechanisms of action)
Block NE reuptake (as well as Na fast channels), so get beta-1 heart stimulation (HR, contractility, conduction velocity), and alpha-1 stimulation (vasoconstriction, ischemia, high BP), which gives unidirectional heart block, CAD, MI. Fast Na channel causes anesthetic effect.
Tolerance in cocaine use?
Can become tolerant to stimulant effects, but not anesthetic effects, so leads to heart block.
Detection of cocaine use?
Usually detected as metabolite in urine (benzoylecgonine). If ethanol is present, forms an active metabolite, ethylbenzoylecgonine, which has a longer half life than the parent drug.
How to treat cocaine overdose?
Stabilize patient. If alive, prognosis is good. IV diazepam for agitation and seizures, ice bath for hyperthermia
Sxs of amphetamine toxicity?
Sympathomimetics (increase monoamine release from synaptic vesicles, block reuptake, and agonize receptors directly). So, leads to HTN, arhythmias, agitation, hyperthermia, paranoia. Street versions are often contaminated with ephedrine, phenylpropanolamine, etc..). If death occurs, it will not be sudden, but several hours after administration
How to treat amphetamine toxicity?
Supportive
Difference between differnet barbiturates for toxicity?
Short acting (pentobarbital and secobarbital) are more potent than long acting (phenobarbital), which also affects interpretation of blood levels. Toxicity causes death by respiratory arrest
What is PCP? Toxicity issues?
Dissociative veterinary anesthetic. Patients can be combative, which requires major sedative like haloperidol to settle down. Positive drug screens should be confirmed by GCMS due tolow prevalence of use.
Toxicity of hallucinogens?
(LSD, Mescaline, marijuana, etc) Not overtly toxic, not detected by most routine tox screens. Behavioral changes are the most dangerous part of use. Powders, papers, and pills are often helpful in identifying exposure to these
MDA and MDMA toxicity?
Ecstasy, an amphetamine analog with similar toxicity (sympathomimetic, so HTN, arhythmias, agitation, hyperthermia, paranoia). Can cause long-term toxicity due to 5HT effects
Fentanyl analog toxicity?
“china white”, alph-methylfentanyl. Very potent opioid effects, treated with naloxone.
MPTP toxicity?
A contaminant or the alternative product formed in the synthesis of MPPP, which is an analogue of meperidine (demerol). MPTP is converted in the body to MPP+, which kills specific neurons, leading to severe Parkinson’s disease.
Digitalis overdose?
Digitalis is a cardiac glycoside used to treat cardiac failure, but not first line due to narrow therapeutic index. It inhibits Na/K ATPase to increase contractility of heart, but toxicity can occur in which there is heart block and N/V. Treated with FAB antibody fragments (Digibind) to inactivate the digoxin
Treatment for digitalis overdose?
Digibind, FAB fragments of antibody used to bind digoxin. However, it can cross-react with digoxin in immunoassays, and can confuse results if treated with Digibind. Serum K+ needs to be monitored too (since K increases with Dig overdose)
Sxs and treatment for carbon monoxide poisoning?
In order of dose, sxs are SOB, cutaneous vasodilation, HA, irritibility, dizziness, nausea, confusion, collapse, syncope, coma, death. Treatment (depends on severity) is fresh air, 100% O2, or hyperbaric Oxygen if necessary.
Sxs of iron poisoning?
metabolic acidosis (by uncoupling oxidative phosphorylation), renal failure. When iron is hydrated, unbuffered hydrogen ions are formed.
Four stages of iron poisoning?
(I) immediate effects: GI problems, metabolic acidosis, hyperglycemia, (II) 6-24 hrs: hypovolemia, hypotension, metabolic acidosis, (III) 12-24 hrs: multiple organ faillure, (IV) 4-6 weeks: gastric scarring, pyloric obstruction, and GI corrosion
What to monitor in iron overdose?
Serum creatinine, Hgb, PT time, LFTs, blood gases. Serial iron levels because peak level may take 24 hrs
Radiograph for iron poisoning?
Positive confirms iron poisoning, but negative doesn’t rule it out.
What dose of elemental iron constitutes moderate risk? High risk?
20-60 mg Fe per kg is moderate. Above 60 is high risk for toxicity
When is deferoxamine indicated for iron poisoning?
If <350mcg/dL, no deferoxamin, just use supportive care. If >350mcg/dL, use deferoxamine continuous IV infusion
How does deferoxamine work?
Chelates iron so it can be renally cleared, giving a “vin rose” color to urine. Half life is about 6 hrs
What are the multisystemic effects of lead poisoning?
HA (and in severe cases encephalopathy), abdominal pain, renal insufficiency, and less commonly gout, motor neuropathy. In children, subclinical effects include neurocognitive deficits, groeth retardation, developmental delay.
Lab tests in lead poisoning?
May show anemia due to less iron going to heme, and instead making increased protoporphyrin IX (Free erythroxyte Protoporphyrin, or FEP), and basophilic stippling. However, plasma lead is the definitive diagnosis
What are long term effects of lead in children?
Demyelination of nerve fibers → peripheral neuropathy (wrist drop) and encephalopathy. Decreased IQ, developmental disturbances
What type of blood fraction used to test for lead?
Whole blood, because 99% of circulating lead is in RBCs. Over 90% of total lead is in bones.
How to treat lead poisoning?
Usually EDTA (chelate lead, excrete in urine), but optimal treatment combines decontamination with supportive care and judicious use of chelating agents. Children with blood lead >45mcg/dL should get chelation. Adults with high lead and symptoms should get chelation. Some clinicians like to use dimercaprol in combo with EDTA. Lead can rebound, so levels need to be monitored for 24-48 hours, and multiple chelation rounds are often necessary.
What is SLUD?
Sxs of carbamate, organophosphate toxicity. It stands for salivation, lacrimation, urination, defaction due to excessive cholinergic stimulation.
How to treat organophosphate/carbamate toxicity?
Atropine (muscarinic antagonist) until drying of pulmonary secretions. Pralidoxime (cholinesterase reactivator) can also be used if within 24 hours of exposure
How to calculate osmol gap?
The sum of [1.86(Na) + glu/18 + BUN/2.8 + 9] substracted from measured osmolality. MEDIE can be reasons for increase
How to calculate osmolality of ethanol from plasma ethanol concentration?
Conc (mg/dL) / 4.6
If blood alcohol is 0.13%, how long to get below 0.10%?
2-3 hours due to the constant rate of 0.01 to 0.02% per hour
Can naloxone be given to comatose opioid overdose patients?
Yes, in any opioid overdose, especially comatose
What is the elemental iron content of FeSO4?
55.8mg Fe/151.9mg FeSO4 (about 1/3)
Tests to perform in iron toxicity?
LFTs, TIBC.
Appearance of blood in iron toxicity?
Icteric (brown/green)
What advantages does TDM (therapeutic drug monitoring) offer?
Compliance analyzed, individual variations in drug disposition identified and dealt with, altered drug utilization due to disease identified, can compensate for physiologic state or differences in metabolism, drug interactions identified easily
Questions to answer before initiating TDM (therapeutic drug monitoring)?
What is benefit, what are the important concentrations (for therapeutic and toxic effects), does the drug have narrow therapeutic range, what is the specificity of the assay, time relationship between dose and sample, clinical value justify cost?
Why TDM necessary for phenytoin?
Has saturated kinetics at therapeutic doses (no increase in effect with increased dose), half life is dose-dependent (8-60 hours, and difficult to determine when steady state is reached (5-30 days). It’s 90-95% protein bound
What does phenytoin do, and what are signs of toxicity?
Antiepileptic, prolongs inactivation of synapse by inactivating Na channels. Can produce nystagmus, drowsiness, ataxia, confusion, tremors, seizures. Chronic administration leads to gingival hyperplasia (40-50% of pts)
When to collect phenytoin levels?
At peak (4-8 hrs after oral dose) and right before next dose (trough). Dose adjustments are empirical
How does theophylline work, and sxs of overdose?
Phosphodiesterase inhibitor, so increases cAMP, cGMP. Increases circulating catecholamines. It is also a competitive inhibitor at adenosine receptors, so leads to bronchial smooth muscle relaxation. 3rd line therapy for asthma. Overdose causes N/V, hypokalemia, hyperglycemia, seizures, tachycardia, anion gap, metabolic acidosis. Treat with charcoal and dialysis. Chronic ingestion more serious than acute toxicity
Why should theophylline be therapeutically monitored?
Pharmacokinetics are age-dependent (3.5 half life in kids, 8-9 hrs in adults). Phenobarbital and phenytoin increase theophylline clearance 2 fold. Primarily cleared in liver.
Whay should depakote be therapeutically monitored?
Valproic acid has fast, complete absorption, but peak concentration is 1-4 hrs after oral dose. Half life varies with age (16 hrs in adults, 8hrs in kids, or 12 hrs in adults with chronic therapy). Half life also increases in hepatic disease.
How does valproic acid work, and sxs of toxicity?
Inhibits GABA transaminase, so increases GABA concentrations. Therapeutic range is 50-100mg/L (trough), but above this leads to hepatic toxicity and encephalopathy
How does phenobarbital work, and sxs of toxicity?
GABAa agonist (hyperpolarizes GABA receptor). Overdose can cause sedation, ataxia, slurred speech, CNS depression (same as primidone, which is metabolized into phenobarbital). Weakness and unsteady gait are common effect.
Why should phenobarbital be therapeutically monitored?
Long elimination half life (70-100 hours), but peak concentration after dose is 1-4 hours. Trough is 10-40mg/L
What is primidone, and why should be therapeutically monitored?
(aka Mysoline) Active metabolite is phenobarbital, so need to measure parent drug and phenobarbital.
Sxs of primidone overdose?
N/V, dizziness, ataxia, CNS depression (exactly same as phenobarbital)
Why should carbamazepine be therapeutically monitored?
“Tegretol”, used commonly for neuropathic pain. Slowly and erratically absorbed, highly protein bound (80%), half life changes with duration of therapy (24 hrs, then 15-20hrs). In children, an active metabolite, carbamazepine-10-11-epoxide, accumulates. Should always do CBC when monitoring carbamazepine.
What are sxs of carbamazepine toxicity?
Blurred vision, nystagmus, ataxia. Also, unrelated to dose is hematological depression (leukopenia, thrombocytopenia, aplastic anemia)
Toxicity effects of ethosuximide?
“Zarontin”, GI distress (well absorbed from GI tract), lethargy, dizziness
Important points about therapeutic monitoring of digoxin?
Must get trough reading 8 hrs post dosing. It is 25% protein bound. It is variably absorbed. Analytically hard to measure due to multiple metabolites and cross reactivity
Effects of digoxin overdose?
Ventricular tachycardia, AV node block, premature ventricular contractions, N/V, green/yellow disturbances
Toxicity of procainamide?
It is an antiarrhythmic, with active metabolite called NAPA (N-acetylprocainamide. NAPA accumulates in people who are fast acetylators, and in renal failure. Sxs include bradycardia, long QRS, AV block, arrhythmias
Examples of aminoglycosides?
Amikacin, gentamicin, tobramycin
For aminoglycosides, why is peak important and why is trough important?
Peak corresponds to therapeutic range, and trough to toxicity.
Toxicity of aminoglycosides?
Ototoxic and nephrotoxic. Cleared mostly renally
Cyclosporine monitoring?
Used as anti-rejection drug for transplants. Has highly variable absorption. Whole blood levels correspond well to therapeutic efficacy. At higher than therapeutic range, it is renally toxic
What drug class is ototoxic and nephrotoxic?
Ototoxic and nephrotoxic (like other vancomycin (similar to other aminoglycosides). Vanco is effective against gram positives. 90% of IV dose excreted renally.
What is sirolimus used for?
Anti-rejection is kidney transplant, inhibits T-cell activation and proliferation in response to cytokines and antigens. It also inhibits antibody production. It is usually given with cyclosporine and corticosteroids initially
Monitoring of sirolimus?
2-4 months after transplant, cyclosporine should be removed and sirolimus increased. It is excreted mainly in feces, half life 62 hours. Adverse effects include hyperXOLemia, hyperTGemia, renal dysfunction, Pneumocystis carnii infection, CMV infection
What is tacrolimus used for?
Prophylaxis of liver or kidney transplant, used concomitantly with corticosteroids. It inhibits T-cell activation (like sirolimus), but should not be used with cyclosporine.
Toxicity of tacrolimus?
Like sirolimus, excreted mainly in feces (90%), is nephrotoxic, causes mild to severe hyperkalemia, so K needs to be monitored. It is also neurotoxic, causing tremor, HA, changes in motor function, mental status. It can also cause HTN, increased CA, and type I DM
Which CYP families most involved in drug metabolism?
CYP1, CYP2, CYP3
Interaction between digoxin and quinidine?
Quinidine inhibits renal clearance of digoxin, so it can go way too high
Interaction between cyclosporine and NSAIDS?
NSAIDS decrease renal clearance, which can already be a problem for many cyclosporine users, so kidneys can get damaged worse, leading to uremia and eventually total renal failure
Salsalate and carbamazepine interaction?
Salsalate displaces carbemazepine from blood proteins (80% bound), causing high free levels of carbamazepine.
Phenobarb and phenytoin interaction?
Phenobarb inhibits phenytoin metabolism, so phenytoin doses should be adjusted accordingly if given together
Which CYP metabolizes phenytoin?
2C9. If a person if homozygous for 2C9*3, they will be a very slow metabolizer of phenytoin, and nedd much lower dose for therapeutic effect
What are Bence Jones Proteins?
Free light chains
What is a monoclonal immunoglobinopathy?
Increased concentration of a single immunoglobulin that originates from a single plasma cell clone. Also known as M-proteins
What is MGUS?
Monoclonal gammopathy of undetermined significance. It is high monoclonal gammaglobins, without clinical evidence of multiple myeloma, macroglobinemia, primary amyloidosis, or other related disorders. Prevalence increases with age. It is a stable condition, characterized by <3g/dL M-protein (monoclonal globulin). There is no back pain, anemia, hypercalcemia, abnormal x-rays, or renal insufficiency. Has low PCLI (plasma cell labeling index), which measures DNA synthesis, and if increases, indicates multiple myeloma has developed or will develop soon.
What is a paraprotein?
Abnormal protein appearing in large quantities as a result of a pathological process.
What is SPEP?
Serum protein elecrophoresis. It is a SCREENING test which can be followed by quanititative assay of specific proteins (Immunoassay). Independent measurement of total proteins is required for conversion to absolute amounts. SPEP is non-specific but is broad spectrum. It separates proteins by size and charge, and is then analyzed with a densitometer to give bands.
What is immunofixation used for?
To identify abnormalities in immunoglobulin fraction
What triggers the largest release of acute phase reactants?
Bacterial infections, due to bacterial endotoxin-induced macrophage release of cytokines that upregulate liver production of the acute phase reactants.. But tissue damage and inflammation, such as from trauma, tissue necrosis, immune-mediated cell damage, and viral infections can also elevate them. Acute phase response occurs in chronic conditions.
Which acute phase reactant is most useful in monitoring acute inflammation and response to treatment for inflammatory conditions?
CRP (C-reactive protein)
What is IFE and when should it be used?
Immunofixation elecrophoresis, is secondary to SPEP
What are immunoassays in identification of protein abnormalities?
Ag/Ab reactions that are quantitative and very sensitive.
Which bands on the SPEP are globulins? Which are acute phase reactants?
Alpha 1, alpha 2, beta, and gamma are all globulins. A typical albumin to globulin ratio is 3:1. Alpha 1, alpha 2, gamma, and some betas are APRs, and all go up with inflammation. Transferrrin is the beta that is not an APR, It is a negative acute phase protein (goes down with inflammation)
What are the alpha1 APRs?
alpha1-antitrypsin (needed for lung elasticity and low concentrations cause hepatocellular damage, if deficient leads to liver disease and emphysema), alpha1-antichymotrypsin, alpha1-glycoprotein (binds drugs)
What are the alpha2 APRs?
Haptoglobin (binds free hemoglobin, and decreases in hemolysis, and is naturally bacteriostatic), ceruloplasmin (binds copper, is low in Wilson’s disease, and is important for Fe storage in ferritin)
what are the gamma APRs
Immunoglobulins, CRP (best inflammatory state marker, used in high sensitivity CRP tests, goes up in cardiac problems, activates complement).
What are the beta APRs?
Fibrinogen and LDL. Transferrin is also a beta protein, but goes down in inflammation (negative APR).
Overall, what changes on electrophoresis are most noticable in inflammation?
alpha1 and alpha2 increase, but albumin, prealbumin, and transferrin go down because they are negative APRs. So, total protein often doesn’t change.
4 types of gamma-globinopathies?
(1) Congenital deficiency, (2) secondary hypogammaglobinemia (protein-losing, malignant lymphomas, leukemias, multiple myeloma), (3) polyclonal hyperimmunoglobinemia (chronic liver disease, chronic infections, malignancies, autoimmune disease, other), (4) monoclonal immunoglobinopathies (multiple myeloma, Waldenstrom’s macroglobinemia, monoclonal gammopathy of undetermined significance “MGUS”)
Where on the electrophoresis does a monoclonal immunoglobinopathy show up (aka M-proteinemia)?
A homogeneous band, giving a discrete peak anywhere in the beta or gamma region, and rarely (1-2%) in the alpha region. It is usually IgG, IgA, IgM, or less commonly IgD
Serum protein characteristics of multiple myeloma?
Can cause monoclonal hyperglobinopathy (M-proteinemia) and sometimes hypogammaglobinemia. M-proteinemia is usually IgG, but can be the others Ig. Bence-Jones proteins (free light chains) can also be present in the urine. In about ¼ of patients, only light chains are made, and no monoclonal peak shows up because they easily pass into urine. Hypogammaglobinemia can occur because overproduction of globulins by malignant cell causes other cells to reduce globulin production, as well as increase catabolism of globulins in the liver.
What is Waldenstrom’s macroglobinemia?
Abnormal IgM, with high sedimentation constant (18S). It is a lymphoid condition, not bone. The blood becomes very viscous because the protein doesn’t leave the plasma. Incidentally, Bence-Jones proteinuria only occurs in 10% of these patients. Spike on SPEP will be on border between beta and gamma, without any other changes to globulins
How often should MGUS patients be tested for M-protein?
Elecrophoresis every 3-6 months. If stable, then every 6-12 months, and if stays stable, every 12 months. Risk of developing MM is 17% at 10 years and 33% at 20 years.
Sxs of multiple myeloma?
Anemia, back pain, hypercalcemia, “punched out” regions of bone on radiograph
Steps in diagnosing/confirming MM?
SPEP, then IFE, then radiograph of bones
Electrophoresis pattern of MM?
Sharp spike in gamma region, indicating M-proteinemia. If it is taller than albumin, it is a bad prognosis. Light chain can also be high due to binding to monoclonal globulin
How are the six lanes of IFE arranged?
Lane 1= total protein, 2=IgG, 3=IgA, 4=IgM, 5=kappa light chain, 6=lambda light chain
If a fibrinogen spike shows up between beta and gamma region in SPEP, what does it indicate?
That a plasma sample, instead of a serum sample was taken. (wrong technique)
What SPEP pattern is indicative of non-specific inflammation?
Low albumin and high alpha1 and alpha2
A very low or absent alpha1 peak on the SPEP indicates what?
alpha1-antitrypsin deficiency. Needs follow-up with a quantitative assay (immunoassay).
What does a very low or absent gamma peak indicate on an SPEP?
Immune deficiency
An SPEP with erratically high alpha2, but low albumin, alpha1, and gamma, indicates what?
Nephrotic syndrome. Urine is high in every fraction (including light chains) except alpha2
What does a beta-gamma bridge on SPEP indicate?
Liver cirrhosis. Also, albumin is low. The bridge is due to high IgA
If SPEP shows large gamma spike, why might the other regions be low?
A monoclonal immunoglobinopathy can often cause decrease in overall globulin synthesis, and increase liver catabolism of globulins
A spike in both the beta and the gamma regions of SPEP indicates what?
Two spikes can be either the rare condition of two different monoclonal proteins, or a monomer and a dimer of IgA. Need IFE to figure out which one.
A sharp spike in the alpha region of SPEP indicates what?
A very rare condition in which there was monoclonal light chain. Must be identified by immunofixation to confirm.
A large sharp peak on border between beta and gamma region of SPEP indicates what?
Waldenstrom’s, due to a monoclonal protein. It also has no marked decrease in globulin production, but albumin may be a little low.
How can MM be treated?
Thalidomide, chemo, radiation
Which Ig is commonly the monoclonal protein in MM? in Waldenstrom’s?
MM usually IgG. Waldenstrom’s is IgM
Why is there rouleaux formation in Waldenstrom’s?
Lack of Ig (partial positive) on RBC membrane (partial negative), so they stick together
Anemia concomitant with a globinopathy is indicative of what?
Possibly MGUS or MM
Possible serious side effect of phenylbutazone?
Agranulocytosis
If SPEP shows low albumin, normal gamma, but high alpha and beta, what might be diagnosis?
Inflammation, maybe from cancer
What is SPEP numbers reveal all normal values (+/- low albumin). But the densitograph shows little or no alpha 1 region?
Probably alpha1-antitrypsin deficiency with lung disease (emphysema)
How would SPEP be affected by chemo and radiation?
Low albumin, and very low to no gamma region. Alpha and beta may be normal.
HLA DR3 and DR4 common is type I or II DM?
Type I. Also, antibodies to beta cells are present in type I, but not in type II.
Which type of DM has raised A1c?
Both
In which type of DM is ketosis common?
Type I
Which type of DM has polyuria, polydipsia, blurred vision as signs of the disease?
Type I and type II
In which type of DM is glucosuria more common?
Type I, but also can occur in type II
In which type of DM is insulin elevated?
Type II has normal to high insulin. Type I has little or no insulin (endogenous)
What do sulfonylureas do?
Increase insulin secretion. Requires beta cell function to work. An example of a sulfonylurea is glipizide
How does metformin work?
Decrease hepatic synthesis of glucose, and reduced postprandial glucose
What do thiazolidinediones do? How do you pronounce that?
Sensitize cells to insulin. “Thy-uh-zole-uh-deen-dy-own”
What does exenatide (Byetta) do?
Enhances glucose-dependent insulin release
What does Symlin do?
Amylin analog. Decreases postprandial increase in glucose and promotes satiety.
What effect does growth hormone have on blood glucose?
Increases glucose by antagonizing insulin
What effect does ACTH have on blood glucose?
Increases glucose by increasing glucocorticoids
What effect do glucocorticoids have on blood glucose?
Increase glucose by gluconeogenesis
What effect does epinephrine have on blood glucose?
Increases glucose by stimulating gluconeogenesis and glycogenolysis. This is the same a glucagon and thyroxine
What effect does glucagon have on blood glucose?
Increases glucose by stimulating gluconeogenesis and glycogenolysis. This is the same a epinephrine and thyroxine
What effect does thyroxine have on blood glucose?
Increases glucose by stimulating gluconeogenesis and glycogenolysis. This is the same a epinephrine and glucagon
What effect does somatostatin have on blood glucose?
Increases glucose by decreasing insulin secretion
Lab findings of type I DM?
Fasting blood glucose >126, glucosuruia, ketonuria, kenotemia, insulinopenia, high glycated hemoglobin, islet cells antibodies (usually during 1st year of diagnosis), increased prevalence of HLA DR3, DR4
Clinical findings of type I DM?
Proneness to ketosis, dependence on injected insulin, frequent onset is in childhood (peak puberty), positive family hx, maybe other autoimmune disease (hypothyroid, hypoadrenalism)
Lab findings of type II DM?
Fasting glucose >126, abnormal glucose tolerance test, variable glucosuria, high glycated hemoglobin, normal to high levels of insulin, decreased insulin receptors
Clinical findings of type II DM?
Ketosis-resistant (usually, unless under stress), insulin-resistant, onset usually >40yo, often associated with obesity, strong family hx
What is criteria for impaired glucose tolerance test (IGT)?
Fasting glucose of 110-126, 2-hr postprandial 140-200

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