Block 7 Flashcards
Chlorpropamide
- 1st gen sulfonylurea
- Closes K+ channel in β-cell memb → depolarization → Ca2+ influx → insulin release
- Use: T2DM
- S/E:
- disulfiram-like effects
- hypoglycemia
- weight gain
- C/I in sulfa allergy
Tolbutamide
- 1st gen sulfonylurea
- Closes K+ channel in β-cell memb → depolarization → Ca2+ influx → insulin release
- Use: T2DM
- S/E:
- disulfiram-like effects
- hypoglycemia
- weight gain
- C/I in sulfa allergy
Glimepiride
- 2nd gen sulfonylurea
- Closes K+ channel in β-cell memb → depolarization → Ca2+ influx → insulin release
- Use: T2DM
- S/E:
- hypoglycemia
- weight gain
- C/I in sulfa allergy
glipizide
- 2nd gen sulfonylurea
- Closes K+ channel in β-cell memb → depolarization → Ca2+ influx → insulin release
- Use: T2DM
- S/E:
- hypoglycemia
- weight gain
- C/I in sulfa allergy
glyburide
- 2nd gen sulfonylurea
- Closes K+ channel in β-cell memb → depolarization → Ca2+ influx → insulin release
- Use: T2DM
- S/E:
- hypoglycemia
- weight gain
- C/I in sulfa allergy
Metformin
- Biguanide
- Stimulates AMPK
- Decreases gluconeogenesis, increases glycolysis & peripheral glucose uptake
- Use: 1st line in T2DM (oral)
- can be used in pts w/o islet fcn
- S/E:
- lactic acidosis (check creatinine)
- weight loss – good for obese pts
- GI upset
- C/I in renal insufficiency
Pioglitazone
- Glitazone / TZD
- Binds to PPAR-γ nuclear transcription regulator → increases periph tissue insulin sensitivity
- Use: mono- or combo therapy in T2DM
- S/E:
- weight gain
- edema
- hepatotoxicity
- HF
- increased risk fractures
rosiglitazone
- Glitazone / TZD
- Binds to PPAR-γ nuclear transcription regulator → increases periph tissue insulin sensitivity
- Use: mono- or combo therapy in T2DM
- S/E:
- weight gain
- edema
- hepatotoxicity
- HF
- increased risk fractures
PPAR-γ
- Nuclear transcription regulator
- Genes activated by PPAR-γ regulate FA storage and glucose metabolism
- Activation of PPAR-γ increases insulin sensitivity and adiponectin levels
Lispro
- Rapid-acting insulin
- Binds insulin receptor (tyrosine kinase activity)
- Use:
- T1DM
- T2DM
- GDM - postprandial
- S/E:
- hypoglycemia
- lipodystrophy
- hypersensitivity (rare)
Aspart
- Rapid-acting insulin
- Binds insulin receptor (tyrosine kinase activity)
- Use:
- T1DM
- T2DM
- GDM - postprandial
- S/E:
- hypoglycemia
- lipodystrophy
- hypersensitivity (rare)
Glulisine
- Rapid-acting insulin
- Binds insulin receptor (tyrosine kinase activity)
- Use:
- T1DM
- T2DM
- GDM - postprandial
- S/E:
- hypoglycemia
- lipodystrophy
- hypersensitivity (rare)
Regular insulin
- Short-acting
- Use:
- T1DM
- T2DM
- GDM
- DKA
- Hyperkalemia
- Stress hyperglycemia
NPH
- Intermediate-Acting Insulin
- Use:
- T1DM
- T2DM
- GDM
Detemir
- Long-acting insulin
- Use:
- T1DM
- T2DM
- GDM - basal control
glargine
- Long-acting (24h) insulin
- Use:
- T1DM
- T2DM
- GDM - basal control
Nateglinide
- Meglitinide
- Binds K+ channels on β-cell memb (different site than sulfonylureas) → postprandial insulin release
- Rapid-acting, short duration – take only w/meal
- Use:
- T2DM monotherapy
- T2DM + metformin
- S/E:
- hypoglycemia
- weight gain
repaglinide
- Meglitinide
- Binds K+ channels on β-cell memb (different site than sulfonylureas) → postprandial insulin release
- Rapid-acting, short duration – take only w/meal
- Use:
- T2DM monotherapy
- T2DM + metformin
- S/E:
- hypoglycemia
- weight gain
Exenatide
- GLP-1 analog
- increases glucose-dependent insulin release + satieity
- decreases glucagon release + gastric emptying
- Use: T2DM
- S/E:
- Nausea/vomiting
- Pancreatitis
- modest weight loss
liraglutide
- GLP-1 analog
- increases glucose-dependent insulin release + satieity
- decreases glucagon release + gastric emptying
- Use: T2DM
- S/E:
- Nausea/vomiting
- Pancreatitis
- modest weight loss
Linagliptin
- DPP-4 inhibitor
- Inhibits DPP-4 enzyme → active GLP-1
- inc glucose-dependent insulin release & satiety
- dec glucagon release & gastric emptying
- Use: T2DM
- S/E:
- Mild urinary or respiratory infections
- weight neutral
saxagliptin
- DPP-4 inhibitor
- Inhibits DPP-4 enzyme → active GLP-1
- inc glucose-dependent insulin release & satiety
- dec glucagon release & gastric emptying
- Use: T2DM
- S/E:
- Mild urinary or respiratory infections
- weight neutral
sitagliptin
- DPP-4 inhibitor
- Inhibits DPP-4 enzyme → active GLP-1
- inc glucose-dependent insulin release & satiety
- dec glucagon release & gastric emptying
- Use: T2DM
- S/E:
- Mild urinary or respiratory infections
- weight neutral
Pramlintide
- Amylin analog
- Decreases glucagon + gastric emptying
- Use:
- T1DM
- T2DM
- S/E:
- Hypoglycemia (w/mistimed prandial insulin)
- nausea
Canagliflozin
- SGLT-2 inhibitor
- Blocks glucose reabsorption in PCT
- Use: T2DM
- S/E:
- Glucosuria
- UTI
- vaginal yeast infxn
- hypERkalemia
- dehydration (→ orthostatic hypOtension)
dapagliflozin
- SGLT-2 inhibitor
- Blocks glucose reabsorption in PCT
- Use: T2DM
- S/E:
- Glucosuria
- UTI
- vaginal yeast infxn
- hypERkalemia
- dehydration (→ orthostatic hypOtension)
empagliflozin
- SGLT-2 inhibitor
- Blocks glucose reabsorption in PCT
- Use: T2DM
- S/E:
- Glucosuria
- UTI
- vaginal yeast infxn
- hypERkalemia
- dehydration (→ orthostatic hypOtension)
Acarbose
- α-glucosidase inhibitor
- Inhibits intestinal brush-border α-glucosidases → delays carb hydrolysis, glucose absorption → decreases postprandial hypERglycemia
- Use: T2DM
- S/E: GI upset
miglitol
- α-glucosidase inhibitor
- Inhibits intestinal brush-border α-glucosidases → delays carb hydrolysis, glucose absorption → decreases postprandial hypERglycemia
- Use: T2DM
- S/E: GI upset
T1DM Rx Strategies
low-carb diet + insulin replacement
T2DM Rx Strategies
- dietary modification and exercise for weight loss
- oral agents
- non-insulin injectables
- insulin replacement
GDM Rx Strategies
- dietary modifications
- exercise
- insulin replacement if lifestyle modification fails
Propylthiouracil (PTU)
- Thioamide
- Blocks thyroid peroxidase → inhibits oxidation of iodide, organification (coupling) of iodine → inhibits thyroid hormone synth
- Blocks 5′-deiodinase → decreases periph T4 to T3 conv
- Use: HypERthyroidism
- Can be used in Pregnancy
- S/E:
- Skin rash
- agranulocytosis (rare)
- aplastic anemia
- hepatotoxicity
Methimazole
- Thioamide
- Blocks thyroid peroxidase → inhibits oxidation of iodide, organification (coupling) of iodine → inhibits thyroid hormone synth
- Use: HypERthyroidism
- S/E:
- Teratogenesis (aplasia cutis)
- Skin rash
- agranulocytosis (rare)
- aplastic anemia
- hepatotoxicity
Levothyroxine
- Synthetic T4
- Use:
- HypOthyroidism
- Myxedema
- Weight loss (off-label)
- S/E:
- Tachycardia
- heat intolerance
- tremors
- arrhythmias
- Interactions:
- Rifampin, Carbamazepine, Phenytoin (enzyme inducers)
- Soy, fiber, coffee, Ca2+ (dec absorp)
- Amiodarone (inhib T4 → T3)
Triiodothyronine
- Synthetic T3
- Use:
- HypOthyroidism
- Myxedema
- Weight loss (off-label)
- S/E:
- Tachycardia
- heat intolerance
- tremors
- arrhythmias
Radioactive iodine (RAI, 131I)
- Concentrates in thyroid gland → follicular necrosis
- Use: most common Rx for hypERthyroidism
- C/I: children, pregnancy/lactation
- S/E: hypOthyroidism
Rx Thyroid Storm
- PTU
- iodides
- propranolol
- corticosteroids
- supportive measures
Thyroid Storm
- Life-threatening medical emergency
- Precipitated by infection, trauma, surgery, withdrawal of antithyroid meds
- Severe thyrotoxicosis, high fever, tachycardia, tachypnea, dehydration, delirium, N/V/D
- Average duration ~72 hours w/treatment
- W/aggressive treatment, mortality is 20%
Iodine
- Lugol’s solution OR saturated potassium iodide solution
- Acutely blocks thyroid hormone release
- inhibits thyroid hormone synth
- decreases gland vascularity
- Use: pre-op before thyroid surgery or after RAI treatment
- Adverse effects:
- hypersensitivity reactions
- iodism (metallic taste, burning mouth, GI upset)
Potassium Iodide
- Competitively inhibits uptake of radioactive iodine
- Use: decrease risk of developing thyroid cancer after exposure to radioactive iodine
Myxedema Coma
- End stage of uncontrolled, long-standing hypOthyroidism
- Advanced hypothyroid symptoms, hypothermia, delirium, and coma
- Mortality 60-70%
Rx Myxedema Coma
- Aggressive treatment:
- IV thyroxine
- glucocorticoids
- supportive measures
- Improvement of symptoms within 24 hrs
- Switch to oral levothyroxine once pt is stable
conivaptan
- ADH antagonist
- Blocks action of ADH at collecting duct V2-receptor
- Use: SIADH
tolvaptan
- ADH antagonist
- Blocks action of ADH at collecting duct V2-receptor
- Use: SIADH
Desmopressin acetate
- Synthetic ADH
- Regulates aquaporin channel insertion in principal cells of collecting duct
- Stimulates endothelial release of vWF → augmentation of platelet binding
- Stabilizes & increases Factor 8 levels
- Use:
- Central DI
- Nocturnal Enuresis
- Type 1 Von Willebrand’s Disease
- Mild Hemophilia A
GH
Use:
- GH deficiency
- Turner Syndrome
Oxytocin
Use:
- Stimulates labor, uterine contractions, milk let-down
- Controls uterine hemorrhage
Somatostatin (octreotide)
- Inhibits GH
- Use:
- Acromegaly
- carcinoid syndrome
- gastrinoma
- glucagonoma
- esophageal varices
Demeclocycline
- ADH antagonist (tetracycline family)
- Use: SIADH
- S/E:
- Nephrogenic DI
- photosensitivity
- abnormalities of bone and teeth
Fludrocortisone
- Synthetic aldosterone analog
- Few glucocorticoid effects
- Use: Mineralocorticoid replacement in 1° adrenal insufficiency
- S/E:
- edema
- HF exacerbation
- hyperpigmentation
- Others similar to glucocorticoids
Cinacalcet
- Sensitizes parathyroid gland Ca2+-sensing receptor to circulating Ca2+ → decreases PTH
- Use: 1° or 2° hyperparathyroidism
- S/E: HypOcalcemia
Lovastatin
- HMG-CoA Reductase inhibitor
- Inhibits conversion of HMG-CoA → mevalonate
- Up-regulates LDL receptors
- Decreases LDL, increases HDL, decreases TG
- Use: Hypercholesterolemia
- Decreases mortality in CAD pts
- S/E:
- Hepatotoxicity / elevated LFTs
- Myopathy (+fibrates or niacin)
- C/I in pregnancy
- CYP3A4 metab
atorvastatin
- HMG-CoA Reductase inhibitor
- Inhibits conversion of HMG-CoA → mevalonate
- Up-regulates LDL receptors
- Decreases LDL, increases HDL, decreases TG
- Use: Hypercholesterolemia
- Decreases mortality in CAD pts
- S/E:
- Hepatotoxicity / elevated LFTs
- Myopathy (+fibrates or niacin)
- C/I in pregnancy
- CYP3A4 metab
simvastatin
- HMG-CoA Reductase inhibitor
- Inhibits conversion of HMG-CoA → mevalonate
- Up-regulates LDL receptors
- Decreases LDL, increases HDL, decreases TG
- Use: Hypercholesterolemia
- Decreases mortality in CAD pts
- S/E:
- Hepatotoxicity / elevated LFTs
- Myopathy (+fibrates or niacin)
- C/I in pregnancy
- CYP3A4 metab
Pravastatin
- HMG-CoA Reductase inhibitor
- Inhibits conversion of HMG-CoA → mevalonate
- Up-regulates LDL receptors
- Decreases LDL, increases HDL, decreases TG
- Use: Hypercholesterolemia
- Decreases mortality in CAD pts
- S/E:
- Hepatotoxicity / elevated LFTs
- Myopathy (+fibrates or niacin)
- C/I in pregnancy
Cholestyramine
- Bile Acid Resin
- Anion exchg in bowel removes bile acids from circ → liver uses cholesterol to make more bile acids + up-regulates LDL receptors
- Decreases LDL, slightly increases HDL + TG
- Use: Hypercholesterolemia
- works best in combo w/statin
- S/E:
- GI upset
- Decreased absorption of other drugs, fat-soluble vitamins
Colestipol
- Bile Acid Resin
- Anion exchg in bowel removes bile acids from circ → liver uses cholesterol to make more bile acids + up-regulates LDL receptors
- Decreases LDL, slightly increases HDL + TG
- Use: Hypercholesterolemia
- works best in combo w/statin
- S/E:
- GI upset
- Decreased absorption of other drugs, fat-soluble vitamins
Colesevalam
- Bile Acid Resin
- Anion exchg in bowel removes bile acids from circ → liver uses cholesterol to make more bile acids + up-regulates LDL receptors
- Decreases LDL, slightly increases HDL + TG
- Use: Hypercholesterolemia
- works best in combo w/statin
- S/E:
- GI upset
- Decreased absorption of other drugs, fat-soluble vitamins
Ezetimibe
- Prevents cholesterol absorption at small intestine brush border
- inhibits NPC1L1 transporter protein
- Decreases LDL
- Use: Hypercholesterolemia
- S/E:
- Rare increase in LFTs
- Diarrhea
Gemfibrozil
- Fibrate
- Upregulates LPL → increases TG clearance
- Activates PPAR-α → induces HDL synth
- Decreases TG, slightly decreases LDL, increases HDL
- Use: Hypercholesterolemia
- S/E:
- Myopathy (+statins)
- Cholesterol gallstones
bezafibrate
- Fibrate
- Upregulates LPL → increases TG clearance
- Activates PPAR-α → induces HDL synth
- Decreases TG, slightly decreases LDL, increases HDL
- Use: Hypercholesterolemia
- S/E:
- Myopathy (+statins)
- Cholesterol gallstones
fenofibrate
- Fibrate
- Upregulates LPL → increases TG clearance
- Activates PPAR-α → induces HDL synth
- Decreases TG, slightly decreases LDL, increases HDL
- Use: Hypercholesterolemia
- S/E:
- Myopathy (+statins)
- Cholesterol gallstones
Niacin / Vitamin B3
- Inhibits lipolysis (hormone-sensitive lipase) in adipose → reduces hepatic VLDL synth
- Decreases LDL, increases HDL, slightly decreases TG
- Use: Hypercholesterolemia
- S/E:
- PG release → Red, flushed face (decreased by NSAIDs, long-term use)
- HypERglycemia
- HypERuricemia
Cyclosporine
- Calcineurin inhibitor
- binds cyclophilin → prevents IL-2 transcription → blocks T-cell activation
- Use:
- Transplant rejection prophylaxis
- psoriasis
- rheumatoid arthritis
- S/E:
- Nephrotoxicity
- HTN
- hyperlipidemia
- neurotoxicity
- gingival hyperplasia
- hirsutism
Tacrolimus (FK506)
- Calcineurin inhibitor
- Binds FK506 binding protein (FKBP) → prevents IL-2 transcription → blocks T-cell activation
- Use: Transplant rejection prophylaxis.
- S/E:
- Nephrotoxicity
- increased risk of diabetes and neurotoxicity
- HTN
- hyperlipidemia
- NO gingival hyperplasia or hirsutism
Sirolimus
- aka Rapamycin
- Binds FKBP → inhibits mTOR
- Use: Kidney transplant rejection prophylaxis
- S/E:
- Pan”Sirtopenia” (pancytopenia)
- insulin resistance
- hyperlipidemia
- NOT nephrotoxic
- Synergistic w/cyclosporine
Rapamycin
- aka Sirolimus
- Binds FKBP → inhibits mTOR
- Use: Kidney transplant rejection prophylaxis
- S/E:
- Pan”Sirtopenia” (pancytopenia)
- insulin resistance
- hyperlipidemia
- NOT nephrotoxic
- Synergistic w/cyclosporine
Daclizumab
- Monoclonal Ab
- Blocks IL-2R
- Use: Kidney transplant rejection prophylaxis
- S/E:
- Edema
- HTN
- tremor
basiliximab
- Monoclonal Ab
- Blocks IL-2R
- Use: Kidney transplant rejection prophylaxis
- S/E:
- Edema
- HTN
- tremor
Azathioprine
- Antimetabolite precursor of 6-mercaptopurine
- Blocks nucleotide synthesis → inhibits lymphocyte prolif
- Use:
- Transplant rejection prophylaxis
- rheumatoid arthritis
- Crohn disease
- glomerulonephritis
- other autoimmune conditions
- S/E:
- Leukopenia
- anemia
- thrombocytopenia
- Toxicity increased by allopurinol (xanthine oxidase degrades 6-MP)
Mycophenolate mofetil
- Reversibly inhibit IMP dehydrogenase → prevent purine synthesis → inhibit B and T cell responses
- Use:
- Transplant rejection prophylaxis
- lupus nephritis
- S/E:
- GI upset
- pancytopenia
- HTN
- hypERglycemia
- Less nephrotoxic and neurotoxic
- Assoc w/invasive CMV infxn
Corticosteroids
- Multiple fcns
- Inhibit NF-κB
- decrease transcription of many cytokines → Suppress both B- and T-cell fcn
- Induce apoptosis of T lymphocytes
- Use:
- Transplant rejection prophylaxis
- many autoimmune and inflamm d/o
- S/E:
- Hyperglycemia
- osteoporosis
- central obesity
- muscle breakdown
- psychosis
- acne
- HTN
- cataracts
- avascular necrosis (femoral head)
- iatrogenic Cushing syndrome.
Aldesleukin
- Recombinant cytokine: IL-2
- Use:
- Renal cell carcinoma
- metastatic melanoma
Epoetin alfa
- Recombinant cytokine: EPO
- Use: Anemias (especially in renal failure)
Filgrastim
- Recombinant cytokine: G-CSF
- Use: Recovery of bone marrow
Sargramostim
- Recombinant cytokine: GM-CSF
- Use: Recovery of bone marrow
IFN-α
- Recombinant cytokine
- Use:
- Chronic hepatitis B and C
- Kaposi sarcoma
- malignant melanoma
IFN-β
- Recombinant cytokine
- Use: Multiple sclerosis
IFN-γ
- Recombinant cytokine
- Use: Chronic granulomatous disease
Romiplostim
- Recombinant cytokine
- thrombopoietin receptor agonist
- Use: Thrombocytopenia
eltrombopag
- Recombinant cytokine
- thrombopoietin receptor agonist
- Use: Thrombocytopenia
Oprelvekin
- Recombinant cytokine: IL-11
- Use: Thrombocytopenia
Immunosuppression targets
Alemtuzumab
- Target: CD52
- Use:
- CLL
- MS
Bevacizumab
- Target: VEGF
- Use:
- Colorectal cancer
- renal cell carcinoma
Cetuximab
- Target: EGFR
- Use:
- Stage IV colorectal cancer
- head and neck cancer
Rituximab
- Target: CD20 (B cells)
- Use:
- B-cell non-Hodgkin lymphoma
- CLL
- rheumatoid arthritis
- ITP
Trastuzumab
- Target: HER2/neu
- Use: Breast cancer
Adalimumab
- Target: Soluble TNF-α
- Use:
- IBD
- rheumatoid arthritis
- ankylosing spondylitis
- psoriasis
certolizumab
- Target: Soluble TNF-α
- Use:
- IBD
- rheumatoid arthritis
- ankylosing spondylitis
- psoriasis
infliximab
- Target: Soluble TNF-α
- Use:
- IBD
- rheumatoid arthritis
- ankylosing spondylitis
- psoriasis
Eculizumab
- Target: Complement protein C5
- Use: Paroxysmal nocturnal hemoglobinuria
Natalizumab
- Target: α4-integrin (WBC adhesion)
- Use:
- Multiple sclerosis
- Crohn disease
- S/E: Risk of PML in pts w/JC virus
Abciximab
- Target: Platelet GPIIb/IIIa
- Use: Antiplatelet agent for prevention of ischemic complications in patients undergoing percutaneous coronary intervention
Denosumab
- Target: RANKL
- inhibits osteoclast maturation (mimics osteoprotegerin)
- Use: Osteoporosis
Digoxin immune Fab
- Target: Digoxin
- Use: Antidote for digoxin toxicity
Omalizumab
- Target: IgE
- prevents IgE binding to FcεRI
- Use: Allergic asthma
Palivizumab
Target: RSV F protein
Use: RSV prophylaxis for high-risk infants
Ranibizumab
- Target: VEGF
- Use: Neovascular age-related macular degeneration
bevacizumab
- Target: VEGF
- Use: Neovascular age-related macular degeneration
Hyperacute Transplant Rejection
- Within minutes
- Pre-existing recipient antibodies react to
- donor antigen (T2HS) → activate complement.
- Widespread thrombosis of graft vessels → ischemia/necrosis.
- Graft must be removed.
Acute Transplant Rejection
- Weeks to months
- Cellular: CD8+ T cells activated against donor MHCs (T4HS)
- Humoral: similar to hyperacute, except Ab’s develop after transplant.
- Vasculitis of graft vessels with dense interstitial lymphocytic infiltrate.
- Prevent/reverse with immunosuppressants.
Chronic Transplant Rejection
- Months to years
- CD4+ T cells respond to recipient APCs presenting donor peptides, including allogeneic MHC.
- Has both cellular and humoral components (T2HS and T4HS).
- Recipient T cells react and secrete cytokines → proliferation of vascular smooth muscle, parenchymal atrophy, interstitial fibrosis.
- Dominated by arteriosclerosis.
Graft-vs-Host Disease
- Timing varies
- Grafted T cells proliferate in immunocompromised host and reject host cells with “foreign” proteins (T4HS) → severe organ dysfcn
- Maculopapular rash, jaundice, diarrhea, hepatosplenomegaly.
- Usually in bone marrow and liver transplants (rich in lymphocytes).
- Potentially beneficial in bone marrow transplant for leukemia (graft-versus-tumor effect).
Bronchiolitis obliterans
Chronic lung graft rejection