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198 Cards in this Set
- Front
- Back
- 3rd side (hint)
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Pathogenesis of Chediak-Higashi sx
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Defect in microtubule polymerization, primarily affecting phagocytosis and neuronal transport (recurrent pyogenic infections, peripheral neuropathy, albinism)
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Pathogenesis of Kartagener's sx
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Dynein arm defect, primarily causing infertility, recurrent respiratory infection, situs inversus
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Pathogenesis of I-cell disease
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Failure to add mannose-6-phosphate to lysosomal proteins, excretion. Causes coarse facies, clouded corneas, arthrogryposis. Fatal in childhood.
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Pathogenesis of Li-Fraumeni sx
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Defect in p53 tumor suppressor protein.
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Pathogenesis of Menke's disease
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Acquired form of Ehlers-Danlos from copper deficiency --> failure of type III collagen
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Hyperextensible skin, easy bruising, hypermobile joints
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Ehlers-Danlos. Watch out for berry aneurysms, SAH, MVP
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Fractures, blue sclerae, hearing loss
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Osteogenesis imperfecta.
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Pathogenesis of Alport's sx
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Defective type IV collagen --> hereditary XR nephritis and deafness
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MR, hyperphagia, obesity, hypogonadism, hypotonia
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Prader-Willi syndrome
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Pathogenesis of Prader-Willi
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Deletion of a normally active Paternal allele on Chr 15
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MR, seizures, ataxia, laughter
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Angelman's syndrome
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Pathogenesis of Angelman's sx
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Deletion of a normally active Maternal allele on Chr 15
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Baby with FTT and crystals in his diaper, megaloblastic anemia
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Orotic acidura. Failure to convert orotic acid to UMP leads to aciduria, from AR orotic acid phosphoryibosyltransferase or orotidine 5'-phosphate decarboxylase.
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Tx for orotic aciduria
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Uridine PO
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Pathogenesis of SCID
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Adenosine deaminase deficiency, leading to adenosine buildup. Negative feedback on de novo purine synthesis, halting of salvage pathway, and directly toxic to WBCs = no nucleic acids to support WBCs
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Child with retardation, self-mutilation, hyperuricemia, gout, choreoathetosis
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Lesch-Nyhan syndrome, defect of HGPRT, leading to failure of NA synthesis and excess uric acid production
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Pathogenesis of xerpderma pigmentosum
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Nucleotide excision repair failure, which in particular the skin is susceptible to from sun damage and dimerization of bases
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Pathogenesis of HNPCC
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Failure of mismatch repair, which removes an entire segment of dmaged nucleotides to have them completely replaced from scratch
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Pathogenesis of beta-thalassemia
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Failure of splicing, which if given the choice is more of a transcriptional problem than a translational problem.
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TPP functions
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"Glycolysis: pyruvate dehydrogenase
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Hi output cardiac failure with neurological symptoms
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Wet Beriberi
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Pathogenesis of B1 deficiency
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Impaired glucose breakdown --> ATP depletion, with highly aerobic tissues hit first.
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B2 function
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Oxidation and reduction (eg FADH2)
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Cheilosis, corneal vascularization
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B2 deficiency
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B3 function
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Part of NAD+
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Glossitis, dermatitis, diarrhea, dementia
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B3 deficiency (pellagra)
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Common causes/pathogeneses of B3 deficiency
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"Hartnup's disease: Tryptophan malabsorption
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Function of B5
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Component of CoA and fatty acid synthase
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Dermatitis, enteritis, alopecia, adrenal insufficiency
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B5 deficiency
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B6 function
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"Cofactor for transamination, decaboxylation, glygocen phosphorylase, cystationine synthesis, heme synthesis
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Seizures, irritability, peripheral neuropathy, sideroblastic anemia, decreased d-ALA
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B6 deficiency
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A function
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Antioxidant, eye pigment component, needed for normal differentiation of epithelial cells. Boosts recovery when given for measles
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Night blindness, dry skin
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A deficiency
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Arthralgias, fatigue, HA, skin changes, sore throat, alopecia, teratogenic
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A excess
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B12 function
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Cofactor for homocysteine methyltransferase and methylmalonyl-CoA mutase
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Macrocytic, megaloblastic anemia, hypersegmented PMNs, neurologic symptoms
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B12 deficiency
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Folate function
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Converted to THF, important for 1-carbon transfers, DNA/RNA synthesis
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Macrocytic, megaloblastic anemia. Neural tube defects in fetuses
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Folate deficiency
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Biotin function
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Carboxylation enzymes: pyruvate, acetyl CoA, propionyl CoA
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Dermatitis, alopecia, enteritis
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Biotin deficiency. Can be caused by excess raw egg white ingestion
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C function
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"Facilitates iron absorption
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Hypercalcemia, hypercalciuria, loss of appetite
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D excess. Seen in sarcoidosis, as D activation is upregulated
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E function
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Antioxidant that protects RBCs against free radical damage
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Hemolytic anemia, muscle weakness, tract demyelination, accelerated atherosclerosis
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E deficiency
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K function
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Gamma-carboxylation. Necessary for factors II, VII, IX, X, protein C, S
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Delayed wound healing, hypogonadism, decreased adult hair, anosmia
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Zinc deficiency
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Pathogenesis of ethanol hypoglycemia
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Dehydrogenating ethanol and then acetaldehyde requires NAD to become NADH, which then builds up. The excess causes a diversion of pyruvate to lactate and OAA to malate, thus shutting down gluconeogenesis in favor of fatty acid synthesis, which leads to hypoglycemia and fatty liver.
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Malnutrition, edema, anemia, fatty liver
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Kwashiorkor
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Uses for NADPH
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Anabolic processes (steroid and FA synthesis); Respiratory burst (WBCs); P-450; Glutathione reductase (RBCs)
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Liver/pancreas substitute for hexokinase, and why
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Glucokinase - has a much higher Km (much lower affinity) but much higher Vmax (capacity) than hexokinase, to allow huge amounts of glucose to be processed fast. Insulin induced, vs hexokinase.
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Role of NAD/NADH in lactate <-> pyruvate <-> TCA balance
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In both, NADH --> NAD+, so either one or the other has to happen, to regenerate NAD+
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Glycolysis ATP requiring steps
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Glc -(hexo/glucokinase)-> G6P; F6P -(PFK-1)-> F1,6BP
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Glycolysis ATP producing steps
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1,3BPG -(phosphoglycerate kin)-> 3PG; Phosphoenolpyruvate -(pyruvate kinase)-> pyruvate
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Effect of citrate on glycolysis
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Downregulates
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Effect of NADH on glycolysis
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Downregulates
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F2,6BP regulation
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In the pancreas, stand in for INSULIN regulation. Insulin (fed state) deactivates cAMP and thus PKA and FBPase-2 while activating PFK-2. More F2,6BP --> Increased PFK-1 activity and more glycolysis. Glucagon works oppositely.
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Effect of alanine on pyruvate kinase
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Downregulates
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Effect of insulin on pyruvate kinase
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Upregulates
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PDH complex requirements and regulation
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Requires TPP (B1), FAD (B2), NAD (B3), CoA (B5), Lipoic acid. Activated by exercise, inhibited by arsenic
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Increased NAD+/NADH ratio, ADP, Ca2+
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Signs of exercise
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PDH deficiency
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Neurologic defects. Tx with ketogenic diet (Lys and Leu) to bypass glycolysis which will be problematic for these pts
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Pyruvate pathway choices
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1. Alanine to carry amino groups b/n liver and muscle; 2. OAA to either the TCA cycle or gluconeogenesis; 3. Acetyl-CoA to the TCA; 4. Lactate for anaerobic metabolism (RBCs, WBCs, kidney medulla, lens, testes, cornea)
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Citrate Is Krebs' Starting Substrate For Making Oxaloacetate
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Citrate Isocitrate a-Ketoglutarate Succinyl-CoA Succinate Fumarate Malate Oxaloacetate
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Krebs output
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3xNADH, 1xFADH2, 2xCO2, 1xGTP per acetyl-CoA (ie x2 for 1 glucose). 1NADH = 3 ATP, 1 FADH2 = 2 ATP, so total is 24 ATP/glucose
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Significance of Isocitrate dehydrogenase in Krebs
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Irreversible, commits acetyl CoA to the Krebs cycle
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Pathway Produces Fresh Glucose
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The irreversible enzymes in gluconeogenesis: Pyruvate carboxylase, PEPCK, F1,6-BPase, G6Pase. Note: only ODD chain FA can produce new glucose this way.
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HMP shunt sites
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Lactating mammary glands, liver, adrenal cortex (FA/steroid synthesis), RBCs
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HMP shunt purpose
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Pulls G6P and makes F6P, same as in glycolysis, but with the additional production of NADPH to use for other reductive reactions
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Pathogenesis of G6PD deficiency
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Without G6PD, can't convert G6P to 2NADPH, ribulose5P (HMP shunt), so no glutathione reduction -> no free radical detox -> hemolytic anemia when under oxidative stress
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T1/2 = ?
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(0.7 x Vd) / Clearance
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LD = ?
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Amount required to fill the Vd to a certain Cp, ie (Vd x Cp)/F
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MD = ?
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Amount required to maintain a certain Cp when fighting a particular Clearance
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Why alkalinize the urine?
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Ionizes weak acids, helps renal excretion. Eg: barbiturates, ASA, MTX
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Why acidify the urine?
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Ionizes weak bases, helps renal excretion. Eg: amphetamines
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Potency vs Efficacy
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Efficacy refers to the highest level of effect (ie % response) that a drug can have whereas potency is the dose of drug you will need to acheive that level of effect, whatever that level is
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How to use therapeutic index
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Higher is safer - LD50/ED50
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Examples of zero-order metabolism
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PEA: Phenytoin, Ethanol, Aspirin
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Tx OD of these with bicarb
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Weak acids: phenobarb, MTX, ASA
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Tx OD of these with ammonium chloride
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Weak bases: Amphetamines (Ammonium cl)
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SNS receptor type of adrenal medulla and sweat glands
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ACh, though otherwise ACh implies a parasympathetic process
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Nicotinic ACh receptors = ?type of protein
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Ligand-gated Na/K channels
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Muscarinic ACh receptors = ?type of receptor
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G-protein coupled receptors
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QISS and QIQ until you're SIQ or SQS
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Mnemonic for G-protein classes: SNS (a/b), PNS (M1-3), Dopa (D1-2), Histamine (H1-2), Vasopressin (V1-2)
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Gq second messengers
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The C's: PLC -> PIP2 -> IP3/DAG -> Ca release and PKC
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Gs second messengers
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The A's: Adenylyl cyclase -> ATP -> cAMP -> PKA
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Gi second messengers
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The A's, as with Gs, but with DECREASED cAMP
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DUMBBELSS
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Cholinesterase inhibitor poisoning (high ACh). Diarrhea Urination Miosis Bronchoconstriction Bradycardia Excitation (muscle and CNS) Lacrimation Salivation Sweating
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Tx for cholinesterase inhibitor poisoning
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Atropine (muscarinic antagonist) and pralidoxime (2PAM, regenerates cholinesterase)
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Atropine effects
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Opposite of the DUMBBELLSS
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Hot as a hare, Dry as a bone, Red as a beet, Blind as a bat, Mad as a hatter
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Atropine OD effects
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Severe orthostatic hypotension, blurred vision, constipation, sexual dysfunction
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Hexamethonium OD effects
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PP effects of epinephrine vs NE
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Epinephrine -> widened PP, whereas NE will have no effect
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The trouble with Norepinephrine
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Causes splanchnic vasoconstriction and decreases renal perfusion
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BB functions
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HTN (cardiac and renin decreased), Angina (decreased heart pumping and O2 use), MI (decreased mortality shown), SVT (slow AV conduction), CHF (slows progression)
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AE of BB
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Asthma exacerbation - use a B1 selective drug like Metoprolol
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Pathogenesis of G6PD deficiency
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Blocked NADPH means no glutathione reductase, which means poor response to oxidative stress in RBCs
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Heinz bodies and bite cells
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G6PD deficiency
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Fructose in the blood and urine
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Fructokinase deficiency, milder than other enzyme deficiencies in fructose metabolism
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Hypoglycemia, jaundice, cirrhosis, vomiting with fructose (sucrose) intake
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Aldolase B deficiency. F1P accumulates, sucking up phosphate groups and causing inhibition of glycogenolysis and gluconeogenesis
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Galactose in the blood and urine, infantile cataracts
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Galactokinase deficiency, milder than other enzyme deficiencies in galactose metabolism
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FTT, jaundice, hepatomegaly, infantile cataracts, MR
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Galactose-1-phosphate uridyltransferase deficiency - cataracts are caused by excess galactitol. As with aldolase B deficiency, sucks up phosphate so glycogenolysis and gluconeogenesis shut down
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Cataracts, retinopathy, peripheral neuropathy, as in chronic hyperglycemia in diabetes (but not)
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Sorbitol gets trapped in the cell, from sorbitol dehydrogenase deficiency (sorbitol = glucose alcohol counterpart) and resulting osmotic damage
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Ordinarily, Careless Crappers Are Also Frivolous About Urination
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UREA cycle: Ornithine + Carbamoyl phosphate -> Citrulline + Aspartate -> Arginosuccinate -> Fumarate (out), Arginine -> Urea -> Kidney
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Increased NH4+ and glutamine with no effect on orotic acid
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Carbamoyl phosphate synthetase I deficiency (no NH4+ -> Carbamoyl phosphate (which in XS is converted to orotic acid and then shunted to pyrimidine synthesis))
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Ammonia intoxication (tremor, slurring, somnolence, vomiting, ICP)
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Hyperammonemia; NH4+ excess depletes a-ketoglutarate -> inhibition of TCA cycle. Tx with limitation of dietary protein, give benzoate, phenylbutyrate, lactulose
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Orotic acid in blood and urine, decreased BUN, hyperammonemia
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OTC deficiency. Later in the pathway than carbamoyl phosphate synthetase and carbamoyl phosphate (which is then converted in XS to orotic acid)
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Phe --> ?
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Tyrosine -> Dopa -> Dopamine, Melatonin -> NE -> Epi
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W --> ?
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Niacin (B6), Serotonin (BH4) -> Melatonin
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Histidine --> ?
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Histamine (B6)
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Glycine --> ?
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Porphyrin (B6) -> Heme
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Arginine --> ?
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Creatine, Urea, NO
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Glutamine --> ?
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GABA (B6), glutathione
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MR, growth retardation, seizures, fair skin, eczema, mousy body odor
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PKU, decreased phenylalanine hydroxylase and resulting buildup of phenylalanine at the cost of tyrosine, dopamine, NE and epinephrine
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Ca/calmodulin, Glucagon, Epinephrine
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Turn ON glycogenolysis
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PKA vs Protein phosphatase
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PKA Activates Glycogen phosphorylase kinase, which Activates glycogenolysis, whereas protein phosphatase does the opposite
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Severe fasting hypoglycemia, increased glycogen in the liver, increased blood lactate, hepatorenomegaly
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Von Gierke's (type I), G6Pase deficiency which means glucose is trapped in the cells as G6P
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Cardiomegaly, liver problems, death
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Pompe's disease (type II), lysosomal a-1,4-glucosidase (acid maltase) deficiency
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Milder form of Von Gierke's, normal blood lactate
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Cori's disease (type III), debranching enzyme deficiency. Gluconeogenesis intact, but will see granules of accumulated limit dextrans
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Painful muscle crams, myoglobinuria with strenuous exercise
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McArdle's (type V), myophophorylase deficiency
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XR LSD
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Fabry's. Remainder are AR
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Fabry's
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a-galactosidase A/Ceramide trihexose
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CV/renal, neuropathy
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Gaucher's
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B-glucocerebrosidase/Glucocerebroside
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Hepatosplenomegaly, aseptic necrosis of femur, bone crises
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Niemann-Pick
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Sphingomyelinase/Sphingomyelin
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Neurodegeneration, hepatosplenomegaly, foam cells
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Tay-Sachs
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Hexosaminidase A/GM2 ganglioside
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Neurodegeneration without hepatosplenomegaly
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Krabbe's
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Galactocerebrosidase/Galactocerebroside
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Optic atrophy, developmental delay, globoid cells
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Metachromatic leukodystrophy
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Arylsulfatase A/Cerebroside sulfate
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Demyelination with ataxia, dementia
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Hurler's
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a-L-iduronidase/Heparan and dermatan sulfate
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Developmental delay, gargoylism, corneal clouding, airway obstruction
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Hunter's
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Iduronate sulfatase/Heparan and dermatan sulfate
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Mild Hurler's, CLEAR eyes
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Mechanism of ketoacidosis in prolonged starvation
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Oxaloacetate is depleted for gluconeogenesis, which stall the TCA and shunts glucose and FFA to ketone body synthesis
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Accelerated atherosclerosis, tendon xanthomas, corneal arcus
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Familial hypercholesterolemia (type IIa). AD deficiency of LDL receptors leading to elevated blood cholesterol levels
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FTT, steatorrhea, acanthocytosis, ataxia, night blindness
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Abeta-lipoproteinemia. AR deficiency of apoB-100 and apoB-48
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NAACP
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Causes of hypereosinophilia: Neoplastic, Asthma, Allergic, Collagen vascular disease, Parasites
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Products of eosinophils
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Histaminase and arylsufatase (limit reaction following mast cell degranulation)
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LTE-4
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Released by basophils
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Mast cell hypersensitivity
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Type I hypersensitivity response, immediate antibody mediated release of histamine
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Itching, flushing, abdominal cramps, PUD
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Systemic mastocytosis, uncontrolled mast cell proliferation -> histamine -> gastric acid secretion
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Langerhans cells
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AKA dendritic cells, on the skin
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Gut lymphatics
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Generally follow the blood supply. In the rectum, there's a difference depending on the pectinate line (internal iliac above/superficial inguinal below)
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Thoracic duct
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To the L subclavian vein (minus R arm/head) is the final destination of almost all the lymph in the body
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Salmonella, S. pneumoniae, H. flu, N. meningitidis
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Encapsulated bacteria that asplenic pts are at higher risk of
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Howell-Jolly bodies in RBCs, thrombocytosis, target cells
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Signs of asplenia
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Hassall's corpuscles
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Medullary thymus structures, unclear function
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T cell positive selection
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Select FOR T cells that DO bind self-MHC
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T cell negative selection
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Select OUT T cells that bind self-MHC TOO strongly
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You see paracortical lymphoid changes,
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You think T-CELLS
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Pathogenesis of pyruvate kinase anemia
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HA, from lack of ATP, which hits RBCs disproportionately because of the high demand for ATP. Extravascular, from rigid RBCs
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Pathogenesis of sickle cell anemia
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Glutamate -> Valine mutation --> aa/b*b* (beta chains are abnormal), causes clumping from altered hydrophobic interactions
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MOA of hydroxyurea
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Increases HbF
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Pathogenesis of HbC
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Glutamate -> Lysine mutation --> milder phenotype than S. HbSC is mixed S and C (mixed presentations)
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Pathogenesis of PNH
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PIGA enzyme makes GPI (RBC membrane anchor binding DAF (decay-accelerating factor)), which inhibits C'. NO PIGA = C'. Worse at night because of slight acidosis while sleeping.
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Increased urine hemosiderin, CD59 negative
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PNH
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Pathogenesis of C3b deficiency
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Affects opsonization, which will make the pt prone to infection of encapsulated bacteria
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Pathogenesis of C3a and C5a deficiency
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Associated with anaphylactic shock. C5a = neutrophil chemotaxis
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Pathogenesis of hereditary angioedema
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C1 esterase inhibitor deficiency
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Location of bili accumulation in kernicterus
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Basal ganglia
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Direct or indirect Coombs to test baby for risk of hemolytic disease?
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Direct: checking baby's RBCs for presence of IgG
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Direct or indirect Coombs to test mom for anti-Rh?
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Indirect: testing mom's serum for anti-Rh antibodies
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Schistocytes (helmet cells)
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Microangiopathic anemia, of any origin
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Maltese cross on blood smear
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Babesiosis, tick-borne infection causing hemolytic anemia
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Acanthocytes
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Liver disease
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Basophilic stippling
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TAIL: thalassemia, ACD, Iron deficiency, Lead poisoning
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Bite cells
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G6PD deficiency
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Elliptocytes
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Hereditary elliptocytosis
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Macro-ovalocyte
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Megaloblastic anemia
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Ringed sideroblasts
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Sideroblastic anemia
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Teardrop cell
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Bone marrow infiltration
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Target cell
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HALT, says the hunter to his target: HbC, Asplenia, Liver disease, Thalassemia
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Fe: low TIBC: high Ferritin: low
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Iron deficiency anemia
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Fe: ~ TIBC: v low Ferritin: high
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Anemia of chronic disease
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Fe: high TIBC: low Ferritin: high
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Hemochromatosis
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Fe: high TIBC: low Ferritin: ~
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Lead poisoning
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Extrinsic pathway
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Tissue factor converts VII --> VIIa, which goes to the jackpot of X --> Xa
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XIIa deficiency
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Not really a problem, not sure why
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Intrinsic pathway cascade
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XII --> XI --> IX (with help from VIII) --> X!
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IX deficiency
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Hemophilia B
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VIIIa deficiency
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Hemophilia A
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HMWK --> ?
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XIIa, Bradykinin --> inflammatory response (vasodilation, permeability, pain), with HELP from Kallikrein (activated by XIIa)
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Kallikrein --> ?
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Activates plasmin (breaks down clot, activates C'), helps activate bradykinin
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Inhibits bradykinin
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ACE
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Vit K factors
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II, VII, IX, X, C, S
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MOA of warfarin
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Blocks Vitamin K epoxide, which is required to activate Vit K
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vWF runs with __?
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VIII
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Protein C and protein S pathway
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S activates C, which INactivates V1 and VIIIa (less clotting)
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Pathogenesis of Factor V Leiden
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Resistant to breakdown by protein C
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@50,000 plt
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Bleeding with trauma
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@15-20,000 plt
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Spontaneous bleeding
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Platelet plug cascade
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vWF binds collagen (GpIb receptor) --> ADP degranulates out of plts --> Stimulates GpIIb/IIIa expression --> Fibrinogen bridging
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TXA2 and platelet plugs
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PRO-aggregation, decrease blood flow
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PGI2 and NO and platelet plugs
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ANTI-aggregation, increase blood flow
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Pathogenesis of von Willebrand's disease
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Defective vWF. Bleeding time is longer, PTT longer (from association with VIII)
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Pathogenesis of Bernard-Soulier
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Decreased Gp1b, impaired plt-plt aggregation
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Pathogenesis of Glanzmann thrombasthenia
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Defective GpIIb/IIIa - impaired plt-plt aggregation
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MOA ASA in plt aggregation
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COX1 and COX2 are irreversibly inhibited - LESS TXA2 = LESS aggregation
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MOA Clopidogrel in plt aggregation
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ADP receptor blockage, LESS ADP = LESS GpIIa/IIIb = LESS aggregation
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MOA Abciximab in plt aggregation
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Inhibits GpIIa/IIIb receptor, which means LESS aggregation
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Macrophage activation cytokine
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IFN-g
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