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Myocardial infarction complications
Cardiac arrhythmia Occurs within the first few days after MI. Important cause of death before reaching the hospital
and within the first 24 hours post-MI.
Postinfarction 1–3 days: friction rub.
fibrinous pericarditis
Papillary muscle 2–7 days: posteromedial papillary muscle rupture A risk due to single blood supply from posterior
rupture descending artery. Can result in severe mitral regurgitation.
Interventricular septal 3–5 days: macrophage-mediated degradation VSD O 2 saturation and pressure in RV.
rupture
Ventricular 3–14 days: free wall rupture contained by adherent pericardium or scar tissue B ; CO, risk of
pseudoaneurysm arrhythmia, embolus from mural thrombus.
formation
Ventricular free wall 5–14 days: free wall rupture C cardiac tamponade. LV hypertrophy and previous MI protect
rupture against free wall rupture. Acute form usually leads to sudden death.
True ventricular 2 weeks to several months: outward bulge with contraction (“dyskinesia”), associated with fibrosis.
aneurysm
Dressler syndrome Several weeks: autoimmune phenomenon resulting in fibrinous pericarditis.
LV failure and Can occur 2° to LV infarction, VSD, free wall rupture, papillary muscle rupture with mitral
pulmonary edema regurgitation.
A B C
Mitral valve
LA
RV LV
Pap
LV
Acute coronary Unstable angina/NSTEMI—Anticoagulation (eg, heparin), antiplatelet therapy (eg, aspirin)
syndrome treatments + ADP receptor inhibitors (eg, clopidogrel), β-blockers, ACE inhibitors, statins. Symptom control
with nitroglycerin and morphine.
STEMI—In addition to above, reperfusion therapy most important (percutaneous coronary
intervention preferred over fibrinolysis).
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Cardiomyopathies
Dilated Most common cardiomyopathy (90% of cases). Leads to systolic dysfunction.
cardiomyopathy Often idiopathic or familial (eg, due to Dilated cardiomyopathy A displays eccentric
mutation of TTN gene encoding the hypertrophy (sarcomeres added in series).
A
sarcomeric protein titin). Takotsubo cardiomyopathy: broken heart
Other etiologies include drugs (eg, alcohol, syndrome—ventricular apical ballooning likely
cocaine, doxorubicin), infection (eg, coxsackie due to increased sympathetic stimulation (eg,
RV LV
B virus, Chagas disease), ischemia (eg, CAD), stressful situations).
systemic conditions (eg, hemochromatosis,
sarcoidosis, thyrotoxicosis, wet beriberi),
peripartum cardiomyopathy.
Findings: HF, S3, systolic regurgitant murmur,
dilated heart on echocardiogram, balloon
appearance of heart on CXR.
+
Treatment: Na restriction, ACE inhibitors,
β-blockers, diuretics, mineralocorticoid
receptor blockers (eg, spironolactone), digoxin,
ICD, heart transplant.
Hypertrophic 60–70% of cases are familial, autosomal Diastolic dysfunction ensues.
obstructive dominant (most commonly due to mutations Marked ventricular concentric hypertrophy
cardiomyopathy in genes encoding sarcomeric proteins, such (sarcomeres added in parallel) B , often septal
as myosin binding protein C and β-myosin predominance. Myofibrillar disarray and
B
heavy chain). Causes syncope during exercise fibrosis.
and may lead to sudden death (eg, in young Physiology of HOCM—asymmetric septal
athletes) due to ventricular arrhythmia. hypertrophy and systolic anterior motion of
RV Findings: S4, systolic murmur. May see mitral mitral valve outflow obstruction dyspnea,
LV
regurgitation due to impaired mitral valve possible syncope.
closure. Other causes of concentric LV hypertrophy:
Treatment: cessation of high-intensity athletics, chronic HTN, Friedreich ataxia.
2+
use of β-blocker or non-dihydropyridine Ca
channel blockers (eg, verapamil). ICD if
syncope occurs.
Restrictive/infiltrative Postradiation fibrosis, Löffler endocarditis, Diastolic dysfunction ensues. Can have low-
cardiomyopathy Endocardial fibroelastosis (thick fibroelastic voltage ECG despite thick myocardium
tissue in endocardium of young children), (especially in amyloidosis).
Amyloidosis, Sarcoidosis, Hemochromatosis Löffler endocarditis—associated with
(although dilated cardiomyopathy is more hypereosinophilic syndrome; histology shows
common) (Puppy LEASH). eosinophilic infiltrates in myocardium.
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Heart failure Clinical syndrome of cardiac pump dysfunction congestion and low perfusion. Symptoms
A include dyspnea, orthopnea, fatigue; signs include S3 heart sound, rales, jugular venous distention
(JVD), pitting edema A .
Systolic dysfunction—reduced EF, EDV; contractility often 2° to ischemia/MI or dilated
cardiomyopathy.
Diastolic dysfunction—preserved EF, normal EDV; compliance ( EDP) often 2° to myocardial
hypertrophy.
Right HF most often results from left HF. Cor pulmonale refers to isolated right HF due to
pulmonary cause.
ACE inhibitors or angiotensin II receptor blockers, β-blockers (except in acute decompensated HF),
and spironolactone mortality. Loop and thiazide diuretics are used mainly for symptomatic
relief. Hydralazine with nitrate therapy improves both symptoms and mortality in select patients.
Left heart failure
Orthopnea Shortness of breath when supine: venous return from redistribution of blood (immediate gravity
effect) exacerbates pulmonary vascular congestion.
Paroxysmal Breathless awakening from sleep: venous return from redistribution of blood, reabsorption of
nocturnal dyspnea peripheral edema, etc.
Pulmonary edema pulmonary venous pressure pulmonary venous distention and transudation of fluid. Presence
of hemosiderin-laden macrophages (“HF” cells) in lungs.
Right heart failure
Hepatomegaly central venous pressure resistance to portal flow. Rarely, leads to “cardiac cirrhosis.”
(nutmeg liver)
Jugular venous venous pressure.
distention
Peripheral edema venous pressure fluid transudation.
HFrEF Contractility ↑ LV contractility
↓
Pressure (mmHg) Pulmonary venous ↑ cardiac
congestion
output
Volume (mL)
Impaired gas Pulmonary ↑ ↑
exchange edema ↑ RV output RAAS sympathetic activity
HFpEF +
Peripheral ↑ systemic ↑ renal Na ↑ LV contractility
venous
Pressure (mmHg) pressure reabsorption
and H O
↓
Compliance
edema
↑
preload
↑
cardiac output
(compensation)
Volume (mL)
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Shock Inadequate organ perfusion and delivery of nutrients necessary for normal tissue and cellular
function. Initially may be reversible but life threatening if not treated promptly.
PCWP SvR
CAuSEd bY SKIN (PRElOAd) CO (AFTERlOAd) TREATMENT
Hypovolemic shock Hemorrhage, dehydration, Cold, IV fluids
burns clammy
Cardiogenic shock Acute MI, HF, valvular Inotropes, diuresis
dysfunction, arrhythmia
Cold, or
Obstructive shock Cardiac tamponade, clammy Relieve obstruction
pulmonary embolism,
tension pneumothorax
Distributive shock Sepsis, anaphylaxis Warm IV fluids, pressors,
CNS injury Dry epinephrine
(anaphylaxis)
Cardiac tamponade Compression of the heart by fluid (eg, blood, effusions [arrows in A ] in pericardial space) CO.
Equilibration of diastolic pressures in all 4 chambers.
A
Findings: Beck triad (hypotension, distended neck veins, distant heart sounds), HR, pulsus
paradoxus. ECG shows low-voltage QRS and electrical alternans B (due to “swinging” movement
RV of heart in large effusion).
LV
Pulsus paradoxus— in amplitude of systolic BP by > 10 mm Hg during inspiration. Seen in
constrictive Pericarditis, obstructive pulmonary disease (eg, Croup, OSA, Asthma, COPD),
cardiac Tamponade (Pea COAT).
B
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Bacterial endocarditis Acute—S aureus (high virulence). Large FROM JANE with ♥:
vegetations on previously normal valves A . Fever
Rapid onset. Roth spots
Subacute—viridans streptococci (low Osler nodes
virulence). Smaller vegetations on congenitally Murmur
abnormal or diseased valves. Sequela of dental Janeway lesions
procedures. Gradual onset. Anemia
Symptoms: fever (most common), new murmur, Nail-bed hemorrhage
Roth spots (round white spots on retina Emboli
surrounded by hemorrhage B ), Osler nodes Requires multiple blood cultures for diagnosis.
(Ouchy raised lesions on finger or toe pads C If culture ⊝, most likely Coxiella burnetii,
due to immune complex deposition), Janeway Bartonella spp.
lesions (small, painless, erythematous lesions Mitral valve is most frequently involved.
on palm or sole) D, splinter hemorrhages E Tricuspid valve endocarditis is associated with
on nail bed. IV drug abuse (don’t “tri” drugs). Associated
Associated with glomerulonephritis, septic with S aureus, Pseudomonas, and Candida.
arterial or pulmonary emboli. S bovis (gallolyticus) is present in colon cancer,
May be nonbacterial (marantic/thrombotic) 2° S epidermidis on prosthetic valves.
to malignancy, hypercoagulable state, or lupus. Native valve endocarditis may be due
to HACEK organisms (Haemophilus,
Aggregatibacter [formerly Actinobacillus],
Cardiobacterium, Eikenella, Kingella).
A B C D E
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Rheumatic fever A consequence of pharyngeal infection with J♥NES (major criteria):
group A β-hemolytic streptococci. Late Joint (migratory polyarthritis)
A
sequelae include rheumatic heart disease, ♥ (carditis)
which affects heart valves—mitral > aortic >> Nodules in skin (subcutaneous)
tricuspid (high-pressure valves affected most). Erythema marginatum (evanescent rash with
Early lesion is mitral valve regurgitation; late ring margin)
lesion is mitral stenosis. Sydenham chorea
Associated with Aschoff bodies (granuloma with
giant cells [blue arrows in A ]), Anitschkow
cells (enlarged macrophages with ovoid,
wavy, rod-like nucleus [red arrow in A ]),
anti-streptolysin O (ASO) and anti-DNase B
titers.
Immune mediated (type II hypersensitivity);
not a direct effect of bacteria. Antibodies to
M protein cross-react with self antigens, often
myosin (molecular mimicry).
Treatment/prophylaxis: penicillin.
Syphilitic heart 3° syphilis disrupts the vasa vasorum of the Can result in aneurysm of ascending aorta or
disease aorta with consequent atrophy of vessel wall aortic arch, aortic insufficiency.
and dilation of aorta and valve ring.
May see calcification of aortic root, ascending
aortic arch, and thoracic aorta. Leads to “tree
bark” appearance of aorta.
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Acute pericarditis Inflammation of the pericardium [ A , red arrows]. Commonly presents with sharp pain, aggravated
by inspiration, and relieved by sitting up and leaning forward. Often complicated by pericardial
A
effusion [between yellow arrows in A ]. Presents with friction rub. ECG changes include
widespread ST-segment elevation and/or PR depression.
Causes include idiopathic (most common; presumed viral), confirmed infection (eg,
coxsackievirus B), neoplasia, autoimmune (eg, SLE, rheumatoid arthritis), uremia, cardiovascular
(acute STEMI or Dressler syndrome), radiation therapy.
Treatment: NSAIDs, colchicine, glucocorticoids, dialysis (uremia).
Myocarditis Inflammation of myocardium global enlargement of heart and dilation of all chambers. Major
cause of SCD in adults < 40 years old.
Presentation highly variable, can include dyspnea, chest pain, fever, arrhythmias (persistent
tachycardia out of proportion to fever is characteristic).
Multiple causes:
Viral (eg, adenovirus, coxsackie B, parvovirus B19, HIV, HHV-6); lymphocytic infiltrate with
focal necrosis highly indicative of viral myocarditis.
Parasitic (eg, Trypanosoma cruzi, Toxoplasma gondii)
Bacterial (eg, Borrelia burgdorferi, Mycoplasma pneumoniae, Corynebacterium diphtheriae)
Toxins (eg, carbon monoxide, black widow venom)
Rheumatic fever
Drugs (eg, doxorubicin, cocaine)
Autoimmune (eg, Kawasaki disease, sarcoidosis, SLE, polymyositis/dermatomyositis)
Complications include sudden death, arrhythmias, heart block, dilated cardiomyopathy, HF, mural
thrombus with systemic emboli.
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314 SECTION III CARDIOvASCuLAR ``CARdIOvASCulAR—PATHOlOGY CARDIOvASCuLAR ``CARdIOvASCulAR—PATHOlOGY
Vasculitides
EPIdEMIOlOGY/PRESENTATION NOTES
Large-vessel vasculitis
Giant cell (temporal) Usually elderly females. Most commonly affects branches of carotid
arteritis Unilateral headache, possible temporal artery artery.
tenderness, jaw claudication. Focal granulomatous inflammation A .
May lead to irreversible blindness due to ESR.
ophthalmic artery occlusion. Treat with high-dose corticosteroids prior to
Associated with polymyalgia rheumatica. temporal artery biopsy to prevent blindness.
Takayasu arteritis Usually Asian females < 40 years old. Granulomatous thickening and narrowing of
“Pulseless disease” (weak upper extremity aortic arch and proximal great vessels B .
pulses), fever, night sweats, arthritis, myalgias, ESR.
skin nodules, ocular disturbances. Treatment: corticosteroids.
Medium-vessel vasculitis
Buerger disease Heavy smokers, males < 40 years old. Segmental thrombosing vasculitis with vein and
(thromboangiitis Intermittent claudication. May lead to nerve involvement.
obliterans) gangrene C , autoamputation of digits, Treatment: smoking cessation.
superficial nodular phlebitis.
Raynaud phenomenon is often present.
Kawasaki disease Asian children < 4 years old. CRASH and burn on a Kawasaki.
(mucocutaneous Conjunctival injection, Rash (polymorphous May develop coronary artery aneurysms E ;
lymph node desquamating), Adenopathy (cervical), thrombosis or rupture can cause death.
syndrome) Strawberry tongue (oral mucositis) D, Hand- Treatment: IV immunoglobulin and aspirin.
foot changes (edema, erythema), fever.
Polyarteritis nodosa Usually middle-aged men. Typically involves renal and visceral vessels, not
Hepatitis B seropositivity in 30% of patients. pulmonary arteries.
Fever, weight loss, malaise, headache. Different stages of transmural inflammation
GI: abdominal pain, melena. with fibrinoid necrosis.
Hypertension, neurologic dysfunction, Innumerable renal microaneurysms F and
cutaneous eruptions, renal damage. spasms on arteriogram (string of pearls
appearance).
Treatment: corticosteroids, cyclophosphamide.
Small-vessel vasculitis
Behçet syndrome High incidence in people of Turkish and eastern Immune complex vasculitis.
Mediterranean descent. Associated with HLA-B51.
Recurrent aphthous ulcers, genital ulcerations,
uveitis, erythema nodosum. Can be
precipitated by HSV or parvovirus. Flares last
1–4 weeks.
Cutaneous small- Occurs 7-10 days after certain medications Immune complex–mediated leukocytoclastic
vessel vasculitis (penicillin, cephalosporins, phenytoin, vasculitis; late involvement indicates systemic
allopurinol) or infections (eg, HCV, HIV). vasculitis.
Palpable purpura, no visceral involvement.
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Vasculitides (continued)
EPIdEMIOlOGY/PRESENTATION NOTES
Small-vessel vasculitis (continued)
Eosinophilic Asthma, sinusitis, skin nodules or purpura, Granulomatous, necrotizing vasculitis with
granulomatosis with peripheral neuropathy (eg, wrist/foot drop). eosinophilia G.
polyangiitis (Churg- Can also involve heart, GI, kidneys (pauci- MPO-ANCA/p-ANCA, IgE level.
Strauss) immune glomerulonephritis).
Granulomatosis Upper respiratory tract: perforation of nasal Triad:
with polyangiitis septum, chronic sinusitis, otitis media, Focal necrotizing vasculitis
(Wegener) mastoiditis. Necrotizing granulomas in lung and upper
Lower respiratory tract: hemoptysis, cough, airway
dyspnea. Necrotizing glomerulonephritis
Renal: hematuria, red cell casts. PR3-ANCA/c-ANCA H (anti-proteinase 3).
CXR: large nodular densities.
Treatment: cyclophosphamide, corticosteroids.
Immunoglobulin A Also called Henoch-Schönlein purpura. Vasculitis 2° to IgA immune complex
vasculitis Most common childhood systemic vasculitis. deposition.
Often follows URI. Associated with IgA nephropathy (Berger
Classic triad: disease).
Skin: palpable purpura on buttocks/legs I Treatment: supportive care, possibly
Arthralgias corticosteroids.
GI: abdominal pain (associated with
intussusception)
Microscopic Necrotizing vasculitis commonly involving No granulomas.
polyangiitis lung, kidneys, and skin with pauci-immune MPO-ANCA/p-ANCA J (anti-
glomerulonephritis and palpable purpura. myeloperoxidase).
Presentation similar to granulomatosis with Treatment: cyclophosphamide, corticosteroids.
polyangiitis but without nasopharyngeal
involvement.
Mixed Often due to viral infections, especially HCV. Cryoglobulins are immunoglobulins that
cryoglobulinemia Triad of palpable purpura, weakness, arthralgias. precipitate in the Cold.
May also have peripheral neuropathy and renal Vasculitis due to mixed IgG and IgM immune
disease (eg, glomerulonephritis). complex deposition.
A B LCC C D E
LM
RSC LCX
LAD
AAo
F G H I J
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316 SECTION III CARDIOvASCuLAR ``CARdIOvASCulAR—PHARMACOlOGY CARDIOvASCuLAR ``CARdIOvASCulAR—PHARMACOlOGY
Cardiac tumors Most common heart tumor is a metastasis (eg, melanoma).
Myxomas Most common 1° cardiac tumor in adults (arrows in A ). 90% occur in the atria (mostly left
atrium). Myxomas are usually described as a “ball valve” obstruction in the left atrium (associated
A
RV with multiple syncopal episodes). IL-6 production by tumor constitutional symptoms (eg, fever,
RA LV weight loss). May auscultate early diastolic “tumor plop” sound. Histology: gelatinous material,
LA myxoma cells immersed in glycosaminoglycans.
Adults make myxed drinks.
Ao
Rhabdomyomas Most frequent 1° cardiac tumor in children (associated with tuberous sclerosis). Histology:
hamartomatous growths.
Kussmaul sign in JVP on inspiration instead of a normal .
Inspiration negative intrathoracic pressure not transmitted to heart impaired filling of right
ventricle blood backs up into vena cava JVD. May be seen with constrictive pericarditis,
restrictive cardiomyopathies, right heart failure, massive pulmonary embolism, right atrial or
ventricular tumors.
Hereditary Also called Osler-Weber-Rendu syndrome. Autosomal dominant disorder of blood vessels. Findings:
hemorrhagic blanching lesions (telangiectasias) on skin and mucous membranes, recurrent epistaxis, skin
telangiectasia discolorations, arteriovenous malformations (AVMs), GI bleeding, hematuria.
` `CARdIOvASCulAR—PHARMACOlOGY
Hypertension treatment
Primary (essential) Thiazide diuretics, ACE inhibitors, angiotensin
hypertension II receptor blockers (ARBs), dihydropyridine
2+
Ca channel blockers.
Hypertension with Diuretics, ACE inhibitors/ARBs, β-blockers β-blockers must be used cautiously in
heart failure (compensated HF), aldosterone antagonists. decompensated HF and are contraindicated in
cardiogenic shock.
In HF, ARBs may be combined with the
neprilysin inhibitor sacubitril.
Hypertension with ACE inhibitors/ARBs, Ca channel blockers, ACE inhibitors/ARBs are protective against
2+
diabetes mellitus thiazide diuretics, β-blockers. diabetic nephropathy.
β-blockers can mask hypoglycemia symptoms.
2+
Hypertension in ARBs, Ca channel blockers, thiazide diuretics, Avoid nonselective β-blockers to prevent
asthma cardioselective β-blockers. β 2 -receptor–induced bronchoconstriction.
Avoid ACE inhibitors to prevent confusion
between drug or asthma-related cough.
Hypertension in Hydralazine, labetalol, methyldopa, nifedipine. “He likes my neonate.”
pregnancy
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CARDIOvASCuLAR ``CARdIOvASCulAR—PHARMACOlOGY CARDIOvASCuLAR ``CARdIOvASCulAR—PHARMACOlOGY SECTION III 317
Cardiac therapy
DIHYDROPYRIDINE G AGONISTS
s
CALCIUM CHANNEL
BLOCKERS
Epi (β ) 2
G AGONISTS Prostaglandins
Amlodipine i Prostacyclin
Clevidipine Fenoldopam (D1)
Nicardipine Epi/NE (α ) 2 Adenosine
Nifedipine
Nimodipine L-type voltage
gated Ca 2+
channel G i G s PDE-3 INHIBITOR
Adenylate
cyclase Milrinone
Action
potential – – Ca 2+
– cAMP AMP
Membrane Ca –calmodulin PDE-3
depolarization
2+
complex
Ca
2+
MLC-kinase
Ca 2+
Sarcoplasmic Ca 2+
reticulum Myosin-P Myosin
CONTRACTION RELAXATION
+ actin + actin
MLC phosphatase PDE-5
IP 3
G cGMP GTP PDE-5 INHIBITOR
q Rho kinase
Sildenafil
L-arginine
Natriuretic
peptide
Gq AGONISTS NO synthase NO receptor NATRIURETIC PEPTIDE
AGONISTS
Epi/NE (α ) 1
Endothelin-1 Bacterial NITRATES ANP
Angiotensin-II Smooth muscle cell LPS NO di usion BNP
Vasopressin Nesiritide
Endothelial cell
L-arginine NO
NO synthase
Acetylcholine
α -agonists
2
Bradykinin
Ca 2+ Cytokines
Histamine
Ca 2+ Serotonin
Receptor(s) Shear stress
Vascular lumen
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Calcium channel Amlodipine, clevidipine, nicardipine, nifedipine, nimodipine (dihydropyridines, act on vascular
blockers smooth muscle); diltiazem, verapamil (non-dihydropyridines, act on heart).
MECHANISM Block voltage-dependent L-type calcium channels of cardiac and smooth muscle muscle
contractility.
Vascular smooth muscle—amlodipine = nifedipine > diltiazem > verapamil.
Heart—verapamil > diltiazem > amlodipine = nifedipine (verapamil = ventricle).
ClINICAl uSE Dihydropyridines (except nimodipine): hypertension, angina (including vasospastic type), Raynaud
phenomenon.
Nimodipine: subarachnoid hemorrhage (prevents cerebral vasospasm).
Nicardipine, clevidipine: hypertensive urgency or emergency.
Non-dihydropyridines: hypertension, angina, atrial fibrillation/flutter.
AdvERSE EFFECTS Gingival hyperplasia.
Dihydropyridine: peripheral edema, flushing, dizziness.
Non-dihydropyridine: cardiac depression, AV block, hyperprolactinemia (verapamil), constipation.
Hydralazine
MECHANISM cGMP smooth muscle relaxation. Vasodilates arterioles > veins; afterload reduction.
ClINICAl uSE Severe hypertension (particularly acute), HF (with organic nitrate). Safe to use during pregnancy.
Frequently coadministered with a β-blocker to prevent reflex tachycardia.
AdvERSE EFFECTS Compensatory tachycardia (contraindicated in angina/CAD), fluid retention, headache, angina,
drug-induced lupus.
Hypertensive Treat with labetalol, clevidipine, fenoldopam, nicardipine, nitroprusside.
emergency
Nitroprusside Short acting vasodilator (arteries = veins); cGMP via direct release of NO. Can cause cyanide
toxicity (releases cyanide).
Fenoldopam Dopamine D 1 receptor agonist—coronary, peripheral, renal, and splanchnic vasodilation. BP,
natriuresis. Also used postoperatively as an antihypertensive. Can cause hypotension and
tachycardia.
Nitrates Nitroglycerin, isosorbide dinitrate, isosorbide mononitrate.
MECHANISM Vasodilate by NO in vascular smooth muscle in cGMP and smooth muscle relaxation.
Dilate veins >> arteries. preload.
ClINICAl uSE Angina, acute coronary syndrome, pulmonary edema.
AdvERSE EFFECTS Reflex tachycardia (treat with β-blockers), hypotension, flushing, headache, “Monday disease” in
industrial exposure: development of tolerance for the vasodilating action during the work week
and loss of tolerance over the weekend tachycardia, dizziness, headache upon reexposure.
Contraindicated in right ventricular infarction, hypertrophic cardiomyopathy, and with
concurrent PDE-5 inhibitor use.
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CARDIOvASCuLAR ``CARdIOvASCulAR—PHARMACOlOGY CARDIOvASCuLAR ``CARdIOvASCulAR—PHARMACOlOGY SECTION III 319
Antianginal therapy Goal is reduction of myocardial O 2 consumption (MVO 2 ) by 1 or more of the determinants of
MVO 2 : end-diastolic volume, BP, HR, contractility.
COMPONENT NITRATES β-blOCKERS NITRATES + β-blOCKERS
End-diastolic volume No effect or No effect or
Blood pressure
Contractility (reflex response) Little/no effect
Heart rate (reflex response) No effect or
Ejection time Little/no effect
MVO 2
Verapamil is similar to β-blockers in effect.
Pindolol and acebutolol are partial β-agonists that should be used with caution in angina.
Ranolazine
MECHANISM Inhibits the late phase of inward sodium current thereby reducing diastolic wall tension and oxygen
consumption. Does not affect heart rate or blood pressure.
ClINICAl uSE Angina refractory to other medical therapies.
AdvERSE EFFECTS Constipation, dizziness, headache, nausea.
Sacubitril
MECHANISM A neprilysin inhibitor; prevents degradation of natriuretic peptides, angiotensin II, and substance P
vasodilation, ECF volume.
ClINICAl uSE Used in combination with valsartan (an ARB) to treat HFrEF.
AdvERSE EFFECTS Hypotension, hyperkalemia, cough, dizziness; contraindicated with ACE inhibitors
due to angioedema.
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320 SECTION III CARDIOvASCuLAR ``CARdIOvASCulAR—PHARMACOlOGY CARDIOvASCuLAR ``CARdIOvASCulAR—PHARMACOlOGY
Lipid-lowering agents
dRuG ldl Hdl TRIGlYCERIdES MECHANISMS OF ACTION AdvERSE EFFECTS/PROblEMS
HMG-CoA reductase Inhibit conversion of HMG- Hepatotoxicity ( LFTs),
inhibitors CoA to mevalonate, a myopathy (esp when
(eg, atorvastatin, cholesterol precursor; used with fibrates or
simvastatin) LDL recycling; niacin)
mortality in CAD patients
Bile acid resins slightly slightly Prevent intestinal GI upset, absorption of
Cholestyramine, reabsorption of bile acids; other drugs and fat-
colestipol, liver must use cholesterol to soluble vitamins
colesevelam make more
Ezetimibe /— /— Prevents cholesterol Rare LFTs, diarrhea
absorption at small intestine
brush border
Fibrates Upregulate LPL TG Myopathy ( risk with
Gemfibrozil, clearance statins), cholesterol
bezafibrate, Activates PPAR-α to induce gallstones (via
fenofibrate HDL synthesis inhibition of cholesterol
7α-hydroxylase)
Niacin Inhibits lipolysis (hormone- Flushed face ( by NSAIDs
sensitive lipase) in adipose or long-term use)
tissue; reduces hepatic Hyperglycemia
VLDL synthesis Hyperuricemia
PCSK9 inhibitors Inactivation of LDL-receptor Myalgias, delirium,
Alirocumab, degradation removal of dementia, other
evolocumab LDL from bloodstream neurocognitive effects
Fish oil and marine slightly slightly at high Believed to decrease FFA Nausea, fish-like taste
omega-3 fatty acids doses delivery to liver and decrease
activity of TG-synthesizing
enzymes
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CARDIOvASCuLAR ``CARdIOvASCulAR—PHARMACOlOGY CARDIOvASCuLAR ``CARdIOvASCulAR—PHARMACOlOGY SECTION III 321
Lipid-lowering agents (continued)
Liver Blood Enterocyte Intestinal lumen
Acetyl-CoA
CHOLESTEROL
HMG-CoA ApoE Lymphatics ABSORPTION
receptor CHY CHY
HMG-CoA CHY
reductase rem Ezetimibe
Mevalonate Triacylglyceride LPL
HDL FFA
pool
Cholesterol Cholesterol
Cholesterol VLDL VLDL FFA FFA
Bile acids Bile acids
MEVALONATE
SYNTHESIS
Niacin BILE ACID
LPL
Statins HDL LPL- REABSORPTION
Lovastatin receptor FFA UPREGULATION
Pravastatin
Simvastatin HDL HDL Bile acid resins
Atorvastatin Lipolysis Fibrates Cholestyramine
Rosuvastatin FFA Gemfibrozil Colestipol
Adipose tissue Bezafibrate Colesevelam
LDL Fenofibrate
LDL
LDL
receptor
ADIPOSE LIPOLYSIS
LDL-RECEPTOR
PCSK9 Niacin
DEGRADATION
PCSK9 inhibitors
Alirocumab
Evolocumab
Cardiac glycosides Digoxin.
+
+
MECHANISM Direct inhibition of Na /K ATPase + 2+ + + Digoxin
Na /Ca
Na /K
indirect inhibition of Na /Ca exchanger. exchanger ATPase
+
2+
2+
[Ca ] i positive inotropy. Stimulates vagus
nerve HR.
Ca 2+
Na + K +
2+
↑TnC Ca ↑ cardiac
2+
SR ↑↑Ca binding contraction
ClINICAl uSE HF ( contractility); atrial fibrillation ( conduction at AV node and depression of SA node).
AdvERSE EFFECTS Cholinergic effects (nausea, vomiting, diarrhea), blurry yellow vision (think van Glow),
arrhythmias, AV block.
Can lead to hyperkalemia, which indicates poor prognosis.
Factors predisposing to toxicity: renal failure ( excretion), hypokalemia (permissive for digoxin
binding at K -binding site on Na /K ATPase), drugs that displace digoxin from tissue-binding
+
+
+
sites, and clearance (eg, verapamil, amiodarone, quinidine).
2+
+
ANTIdOTE Slowly normalize K , cardiac pacer, anti-digoxin Fab fragments, Mg .
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322 SECTION III CARDIOvASCuLAR ``CARdIOvASCulAR—PHARMACOlOGY CARDIOvASCuLAR ``CARdIOvASCulAR—PHARMACOlOGY
Antiarrhythmics— Slow or block () conduction (especially in depolarized cells). slope of phase 0 depolarization. Are
sodium channel state dependent (selectively depress tissue that is frequently depolarized [eg, tachycardia]).
blockers (class I)
Class IA Quinidine, Procainamide, Disopyramide.
“The Queen Proclaims Diso’s pyramid.” 0 mV
Slope of
+
MECHANISM Moderate Na channel blockade. 0 mV
phase 0
AP duration, effective refractory period 0 mV I Na
(ERP) in ventricular action potential, QT Slope of
phase 0
Slope of
I
interval, some potassium channel blocking phase 0
Na
effects. I Na
ClINICAl uSE Both atrial and ventricular arrhythmias,
especially re-entrant and ectopic SVT and VT.
AdvERSE EFFECTS Cinchonism (headache, tinnitus with
quinidine), reversible SLE-like syndrome
(procainamide), HF (disopyramide),
thrombocytopenia, torsades de pointes due to 0 mV
QT interval. Slope of
phase 0
Class IB Lidocaine, MexileTine. 0 mV I Na
“I’d Buy Liddy’s Mexican Tacos.” 0 mV Slope of
phase 0
Slope of
I
Na
+
MECHANISM Weak Na channel blockade. phase 0
I
Na
AP duration. Preferentially affect ischemic or
depolarized Purkinje and ventricular tissue.
Phenytoin can also fall into the IB category.
ClINICAl uSE Acute ventricular arrhythmias (especially post-
MI), digitalis-induced arrhythmias.
IB is Best post-MI.
AdvERSE EFFECTS CNS stimulation/depression, cardiovascular
depression. 0 mV
Class IC Flecainide, Propafenone. Slope of
“Can I have Fries, Please.” 0 mV
phase 0
0 mV I
Na
+
MECHANISM Strong Na channel blockade. Slope of
phase 0
Significantly prolongs ERP in AV node and Slope of
I
Na
accessory bypass tracts. No effect on ERP in phase 0
I
Na
Purkinje and ventricular tissue.
Minimal effect on AP duration.
ClINICAl uSE SVTs, including atrial fibrillation. Only as a last
resort in refractory VT.
AdvERSE EFFECTS Proarrhythmic, especially post-MI
(contraindicated). IC is Contraindicated in
structural and ischemic heart disease.
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CARDIOvASCuLAR ``CARdIOvASCulAR—PHARMACOlOGY CARDIOvASCuLAR ``CARdIOvASCulAR—PHARMACOlOGY SECTION III 323
Antiarrhythmics— Metoprolol, propranolol, esmolol, atenolol, timolol, carvedilol.
β-blockers (class II)
2+
MECHANISM Decrease SA and AV nodal activity by cAMP, Ca currents. Suppress abnormal pacemakers by
slope of phase 4.
AV node particularly sensitive— PR interval. Esmolol very short acting.
ClINICAl uSE SVT, ventricular rate control for atrial fibrillation and atrial flutter.
AdvERSE EFFECTS Impotence, exacerbation of COPD and asthma, cardiovascular effects (bradycardia, AV block, HF),
CNS effects (sedation, sleep alterations). May mask the signs of hypoglycemia.
Metoprolol can cause dyslipidemia. Propranolol can exacerbate vasospasm in vasospastic angina.
β-blockers (except the nonselective α- and β-antagonists carvedilol and labetalol) cause unopposed
α 1 -agonism if given alone for pheochromocytoma or for cocaine toxicity (unsubstantiated). Treat
β-blocker overdose with saline, atropine, glucagon.
60 Decrease slope Prolonged
repolarization
of phase 4
Membrane potential (mv) –30 0 Threshold
depolarization
(at AV node)
30
potential
–60
–90
0 100 200 300 400 500 600 700 800
Time (ms)
Pacemaker cell action potential
Antiarrhythmics— Amiodarone, Ibutilide, Dofetilide, Sotalol. AIDS.
potassium channel
blockers (class III)
MECHANISM AP duration, ERP, QT interval.
ClINICAl uSE Atrial fibrillation, atrial flutter; ventricular
tachycardia (amiodarone, sotalol).
AdvERSE EFFECTS Sotalol—torsades de pointes, excessive β Remember to check PFTs, LFTs, and TFTs when
blockade. using amiodarone.
Ibutilide—torsades de pointes. Amiodarone is lipophilic and has class I, II, III,
Amiodarone—pulmonary fibrosis, and IV effects.
hepatotoxicity, hypothyroidism or
hyperthyroidism (amiodarone is 40% iodine by
weight), acts as hapten (corneal deposits, blue/
gray skin deposits resulting in photodermatitis),
neurologic effects, constipation, cardiovascular
effects (bradycardia, heart block, HF).
0 mV
Markedly prolonged
repolarization (I )
K
−85 mV
Cell action potential
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324 SECTION III CARDIOvASCuLAR ``CARdIOvASCulAR—PHARMACOlOGY
Antiarrhythmics— Diltiazem, Verapamil
calcium channel
blockers (class IV)
MECHANISM Decrease conduction Velocity, ERP, PR interval.
ClINICAl uSE Prevention of nodal arrhythmias (eg, SVT), rate control in atrial fibrillation.
AdvERSE EFFECTS Constipation, flushing, edema, cardiovascular effects (HF, AV block, sinus node depression).
60 Slow rise of Prolonged
Membrane potential (mv) –30 0 repolarization Threshold
30
action potential
(at AV node)
–60
–90 potential
0 100 200 300 400 500 600 700
Time (ms)
Other antiarrhythmics
+
Adenosine K out of cells hyperpolarizing the cell and I Ca , decreasing AV node conduction. Drug of
choice in diagnosing/terminating certain forms of SVT. Very short acting (~ 15 sec). Effects
blunted by theophylline and caffeine (both are adenosine receptor antagonists). Adverse effects
include flushing, hypotension, chest pain, sense of impending doom, bronchospasm.
Magnesium Effective in torsades de pointes and digoxin toxicity.
Ivabradine
MECHANISM IVabradine prolongs slow depolarization (phase “IV”) by selectively inhibiting “funny” sodium
channels (I f ).
ClINICAl uSE Chronic stable angina in patients who cannot take β-blockers. Chronic HFrEF.
AdvERSE EFFECTS Luminous phenomena/visual brightness, hypertension, bradycardia.
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HIGH-YIELD SY STEMS
SEC TION III
Endocrine
DO not delete, used for running headers
“If you skew the endocrine system, you lose the pathways to self.” `Embryology 326
—Hilary Mantel
`Anatomy 327
“We have learned that there is an endocrinology of elation and despair, a
chemistry of mystical insight, and, in relation to the autonomic nervous `Physiology 328
system, a meteorology and even . . . an astro-physics of changing moods.”
—Aldous Huxley `Pathology 338
“Chocolate causes certain endocrine glands to secrete hormones that affect `Pharmacology 352
your feelings and behavior by making you happy.”
—Elaine Sherman, Book of Divine Indulgences
The endocrine system comprises widely distributed organs that work in a
highly integrated manner to orchestrate a state of hormonal equilibrium
within the body. Generally speaking, endocrine diseases can be
classified either as diseases of underproduction or overproduction,
or as conditions involving the development of mass lesions—which
themselves may be associated with underproduction or overproduction
of hormones. Therefore, study the endocrine system first by learning the
glands, their hormones, and their regulation, and then by integrating
disease manifestations with diagnosis and management. Take time to
learn the multisystem connections.
325
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326 SEcTion iii EndocrinE ` endocrine—embryology EndocrinE ` endocrine—AnAtomy
` endocrine—embryology
Thyroid development Thyroid diverticulum arises from floor of primitive pharynx and descends into neck. Connected to
A tongue by thyroglossal duct, which normally disappears but may persist as cysts or the pyramidal
lobe of thyroid. Foramen cecum is normal remnant of thyroglossal duct.
Most common ectopic thyroid tissue site is the tongue (lingual thyroid). Removal may result in
hypothyroidism if it is the only thyroid tissue present.
Thyroglossal duct cyst A presents as an anterior midline neck mass that moves with swallowing
or protrusion of the tongue (vs persistent cervical sinus leading to pharyngeal cleft cyst in lateral
neck).
Thyroid follicular cells derived from endoderm.
Foramen cecum
Hyoid bone
Thyrohyoid membrane
Internal carotid artery
Thyroglossal duct
External carotid artery
Thyroid cartilage
Superior thyroid artery
Thyroid Inferior thyroid artery
Trachea
Left subclavian artery
Brachiocephalic artery
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EndocrinE ` endocrine—embryology EndocrinE ` endocrine—AnAtomy SEcTion iii 327
` endocrine—AnAtomy
Pituitary gland
Anterior pituitary Secretes FSH, LH, ACTH, TSH, prolactin, Proopiomelanocortin derivatives—β-endorphin,
(adenohypophysis) GH, and β-endorphin. Melanotropin (MSH) ACTH, and MSH. Go pro with a BAM!
secreted from intermediate lobe of pituitary. FLAT PiG: FSH, LH, ACTH, TSH, PRL, GH.
Derived from oral ectoderm (Rathke pouch). B-FLAT: Basophils—FSH, LH, ACTH, TSH.
α subunit—hormone subunit common to Acid PiG: Acidophils — PRL, GH.
TSH, LH, FSH, and hCG.
β subunit—determines hormone specificity.
Posterior pituitary Stores and releases vasopressin (antidiuretic
(neurohypophysis) hormone, or ADH) and oxytocin, both
made in the hypothalamus (supraoptic and
paraventricular nuclei) and transported to
posterior pituitary via neurophysins (carrier
proteins). Derived from neuroectoderm.
Adrenal cortex and Adrenal cortex (derived from mesoderm) and medulla (derived from neural crest).
medulla
HORMONE 1˚ HORMONE
ANATOMY HISTOLOGY 1˚ REGULATION BY CLASS PRODUCED
Zona Glomerulosa Angiotensin II Mineralocorticoids Aldosterone
Adrenal gland
CORTEX Zona Fasciculata ACTH, CRH Glucocorticoids Cortisol
Capsule
ACTH, CRH Androgens DHEA
Zona Reticularis
Preganglionic
Superior surface MEDULLA Chroma n cells sympathetic fibers Catecholamines Epi, NE
of kidney
GFR corresponds with Salt (mineralocorticoids), Sugar (glucocorticoids), and Sex (androgens).
“The deeper you go, the sweeter it gets.”
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328 SEcTion iii EndocrinE ` endocrine—Physiology EndocrinE ` endocrine—Physiology
` endocrine—Physiology
Hypothalamic-pituitary hormones
hormone FUnction clinicAl notes
ADH water permeability of distal convoluted tubule Stimulus for secretion is plasma osmolality,
and collecting duct cells in kidney to water except in SIADH, in which ADH is elevated
reabsorption despite plasma osmolality
CRH ACTH, MSH, β-endorphin in chronic exogenous steroid use
Dopamine prolactin, TSH Also called prolactin-inhibiting factor
Dopamine antagonists (eg, antipsychotics) can
cause galactorrhea due to hyperprolactinemia
GHRH GH Analog (tesamorelin) used to treat
HIV-associated lipodystrophy
GnRH FSH, LH Suppressed by hyperprolactinemia
Tonic GnRH analog (eg, leuprolide) suppresses
hypothalamic–pituitary–gonadal axis.
Pulsatile GnRH leads to puberty, fertility
MSH melanogenesis by melanocytes Causes hyperpigmentation in Cushing disease,
as MSH and ACTH share the same precursor
molecule, proopiomelanocortin
Oxytocin Causes uterine contractions during labor. Modulates fear, anxiety, social bonding, mood,
Responsible for milk letdown reflex in response and depression
to suckling.
Prolactin GnRH Pituitary prolactinoma amenorrhea,
Stimulates lactogenesis. osteoporosis, hypogonadism, galactorrhea
Breastfeeding prolactin GnRH
delayed postpartum ovulation (natural
contraception)
Somatostatin GH, TSH Also called growth hormone inhibiting hormone
(GHIH)
Analogs used to treat acromegaly
TRH TSH, prolactin TRH (eg, in 1°/2° hypothyroidism) may
increase prolactin secretion galactorrhea
Hypothalamus CRH GnRH TRH Somatostatin GHRH DA
Anterior
pituitary ACTH LH FSH TSH GH Prolactin
Basophils (basophilic) Acidophils (eosinophilic)
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EndocrinE ` endocrine—Physiology EndocrinE ` endocrine—Physiology SEcTion iii 329
Growth hormone
Also called somatotropin. Secreted by anterior
Sleep, hypoglycemia, stress Aging, obesity, glucose pituitary.
GHRH Stimulates linear growth and muscle mass
Somatostatin
through IGF-1 (somatomedin C) secretion by
liver. insulin resistance (diabetogenic).
Released in pulses in response to growth
hormone–releasing hormone (GHRH).
Secretion during exercise, deep sleep, puberty,
Posterior hypoglycemia, CKD.
Anterior pituitary Secretion by glucose, somatostatin,
pituitary somatomedin (regulatory molecule secreted
by liver in response to GH acting on target
tissues).
Growth Excess secretion of GH (eg, pituitary adenoma)
hormone
may cause acromegaly (adults) or gigantism
(children). Treatment: somatostatin analogs
(eg, octreotide) or surgery.
Amino acid uptake IGF-1 Amino acid uptake Glucose uptake
Protein synthesis Protein synthesis Lipolysis
DNA and RNA synthesis
Chondroitin sulfate
Collagen
Cell size and number
Antidiuretic hormone Also called vasopressin.
soUrce Synthesized in hypothalamus (supraoptic and
paraventricular nuclei), stored and secreted by
posterior pituitary.
FUnction Regulates b1ood pressure (V 1 -receptors) and ADH level is in central diabetes insipidus (DI),
serum osmolality (V 2 -receptors). Primary normal or in nephrogenic DI.
function is serum osmolality regulation (ADH Nephrogenic DI can be caused by mutation in
serum osmolality, urine osmolality) via V 2 -receptor.
regulation of aquaporin channel insertion in Desmopressin (ADH analog) is a treatment for
principal cells of renal collecting duct. central DI and nocturnal enuresis.
regUlAtion Plasma osmolality (1°); hypovolemia.
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330 SEcTion iii EndocrinE ` endocrine—Physiology EndocrinE ` endocrine—Physiology
Prolactin
soUrce Secreted mainly by anterior pituitary. Structurally homologous to growth hormone.
FUnction Stimulates milk production in breast; inhibits Excessive amounts of prolactin associated with
ovulation in females and spermatogenesis libido.
in males by inhibiting GnRH synthesis and
release.
regUlAtion Prolactin secretion from anterior pituitary Dopamine agonists (eg, bromocriptine) inhibit
is tonically inhibited by dopamine from prolactin secretion and can be used in
tuberoinfundibular pathway of hypothalamus. treatment of prolactinoma.
Prolactin in turn inhibits its own secretion Dopamine antagonists (eg, most antipsychotics,
by dopamine synthesis and secretion from metoclopramide) and estrogens (eg, OCPs,
hypothalamus. TRH prolactin secretion (eg, pregnancy) stimulate prolactin secretion.
in 1° or 2° hypothyroidism).
Sight/cry of baby Higher cortical centers
Hypothalamus
Medications
Chest wall injury (via ANS) Dopamine TRH 1° hypothyroidism
Nipple stimulation
Posterior
Anterior pituitary
pituitary
Estrogen Pregnancy
Reduced prolactin
elimination FSH
Prolactin GnRH Ovulation
Renal failure Spermatogenesis
LH
Milk production
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EndocrinE ` endocrine—Physiology EndocrinE ` endocrine—Physiology SEcTion iii 331
Thyroid hormones Thyroid produces triiodothyronine (T 3 ) and thyroxine (T 4 ), iodine-containing hormones that
control the body’s metabolic rate.
soUrce Follicles of thyroid. 5′-deiodinase converts T 4 (the major thyroid product) to T 3 in peripheral tissue
(5, 4, 3). Peripheral conversion is inhibited by glucocorticoids, β-blockers, and propylthiouracil
(PTU). Reverse T 3 (rT 3 ) is a metabolically inactive byproduct of the peripheral conversion of T 4
and its production is increased by growth hormone and glucocorticoids. Functions of thyroid
peroxidase include oxidation, organification of iodine, and coupling of monoiodotyrosine (MIT)
and diiodotyrosine (DIT). Inhibited by PTU and methimazole. DIT + DIT = T 4 . DIT + MIT =
T 3 . Wolff-Chaikoff effect—excess iodine temporarily turns off thyroid peroxidase T 3 /T 4
production (protective autoregulatory effect).
FUnction Only free hormone is active. T 3 binds nuclear receptor with greater affinity than T 4 . T 3 functions
—7 B’s:
Brain maturation
Bone growth (synergism with GH)
β-adrenergic effects. β 1 receptors in heart CO, HR, SV, contractility; β-blockers alleviate
adrenergic symptoms in thyrotoxicosis
+
+
Basal metabolic rate (via Na /K -ATPase activity O 2 consumption, RR, body temperature)
Blood sugar ( glycogenolysis, gluconeogenesis)
Break down lipids ( lipolysis)
Stimulates surfactant synthesis in Babies
regUlAtion TRH ⊕ TSH release ⊕ follicular cells. Thyroid-stimulating immunoglobulin (TSI) may ⊕
follicular cells in Graves disease.
Negative feedback primarily by free T 3 /T 4 :
Anterior pituitary sensitivity to TRH
Hypothalamus TRH secretion
Thyroxine-binding globulin (TBG) binds most T 3 /T 4 in blood. Bound T 3 /T 4 = inactive.
TBG in pregnancy, OCP use (estrogen TBG) total T 3 /T 4
TBG in steroid use, nephrotic syndrome
Hypothalamus
Peripheral tissue Blood Thyroid follicular epithelial cell Follicular lumen
TRH
TG TG
Tyrosine
Thyroglobulin
+
Anterior pituitary I – I – Oxidation I 2
Somatostatin Na + Organification
TSH Downstream thyroid Thyroid
function Deiodinase peroxidase MIT
PTU, TG MIT
methimazole DIT
MIT, DIT DIT
Thyroid follicular cells
Thyroid Coupling
peroxidase reaction
TSI T
T , T 3 MIT MIT
DIT
3 4 T T T > T TG DIT TG DIT
3 4 4 3 T 3 T 3
5'-deiodinase (to circulation) Proteases Endocytosis
T 4 T 4
PTU
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332 SEcTion iii EndocrinE ` endocrine—Physiology EndocrinE ` endocrine—Physiology
Parathyroid hormone
soUrce Chief cells of parathyroid
2+
3–
2+
FUnction free Ca in the blood (1° function) PTH serum Ca , serum PO 4 , urine
3–
3–
2+
Ca and PO 4 absorption in GI system PO 4 , urine cAMP
2+
3–
Ca and PO 4 from bone resorption RANK-L (receptor activator of NF-κB ligand)
2+
Ca reabsorption from DCT secreted by osteoblasts and osteocytes; binds
3–
PO 4 reabsorption in PCT RANK (receptor) on osteoclasts and their
2+
1,25-(OH) 2 D 3 (calcitriol) production by precursors to stimulate osteoclasts and Ca
activating 1α-hydroxylase in PCT bone resorption (intermittent PTH release
Tri to make D 3 in the PCT can also stimulate bone formation)
PTH = Phosphate-Trashing Hormone
PTH-related peptide (PTHrP) functions
like PTH and is commonly increased in
malignancies (eg, squamous cell carcinoma of
the lung, renal cell carcinoma)
2+
regUlAtion serum Ca PTH secretion
3−
serum PO 4 PTH secretion
2+
serum Mg PTH secretion
2+
serum Mg PTH secretion
2+
Common causes of Mg include diarrhea,
aminoglycosides, diuretics, alcohol abuse
PTH activity
2+
3–
↓ ionized Ca , ↑ PO , or 1,25-(OH) D
4 2 3
↑
Four
para- Vitamin D activity
thyroid
Feedback glands
inhibition 25-OH D 3
of PTH
synthesis
PTH released PO 3–
into circulation ↑ 4
1α-hydroxylase
↑ 1,25-(OH) D
2 3
1,25-(OH) D 3
2
Renal tubular cells
Bone Intestines
2+
↑ 1,25-(OH) D synthesis ↑ Ca and ↑ PO 4 3– ↑ absorption of
2
3
3–
2+
Reabsorption: ↑ Ca , PO 4 3– released from bone Ca and PO
2+
4
↑
Urine Ca , ↑ PO 3–
2+
4
↑
↑ Ca and ↑ PO 3–
2+
4
2+
↑ Ca and PO 3–
4
↑
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EndocrinE ` endocrine—Physiology EndocrinE ` endocrine—Physiology SEcTion iii 333
+
2+
Calcium homeostasis Plasma Ca exists in three forms: pH (less H ) albumin binds more
2+
2+
Ionized/free (~ 45%, active form) Ca ionized Ca (eg, cramps, pain,
Bound to albumin (∼ 40%) paresthesias, carpopedal spasm) PTH
+
2+
Bound to anions (∼ 15%) pH (more H ) albumin binds less Ca
2+
ionized Ca PTH
2+
Ionized/free Ca is 1° regulator of PTH;
changes in pH alter PTH secretion, whereas
changes in albumin concentration do not
Calcitonin
soUrce Parafollicular cells (C cells) of thyroid. Calcitonin opposes actions of PTH. Not
2+
important in normal Ca homeostasis
2+
FUnction bone resorption of Ca . Calcitonin tones down serum Ca levels and
2+
2+
regUlAtion serum Ca calcitonin secretion.
keeps it in bones
Glucagon
soUrce Made by α cells of pancreas.
FUnction Promotes glycogenolysis, gluconeogenesis, lipolysis, ketogenesis. Elevates blood sugar levels to
maintain homeostasis when bloodstream glucose levels fall too low (ie, fasting state).
regUlAtion Secreted in response to hypoglycemia. Inhibited by insulin, hyperglycemia, somatostatin.
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334 SEcTion iii EndocrinE ` endocrine—Physiology EndocrinE ` endocrine—Physiology
Insulin
synthesis Preproinsulin (synthesized in RER of pancreatic β cells) cleavage of “presignal” proinsulin
Proinsulin (stored in secretory granules) cleavage of proinsulin exocytosis of insulin and C-peptide
C-peptide
equally. Insulin and C-peptide are in insulinoma and sulfonylurea use, whereas exogenous insulin
S α-chain lacks C-peptide.
S
S
S S
S
β-chain
FUnction Binds insulin receptors (tyrosine kinase Insulin-dependent glucose transporters:
activity ), inducing glucose uptake (carrier- GLUT4: adipose tissue, striated muscle
mediated transport) into insulin-dependent (exercise can also GLUT4 expression)
tissue and gene transcription. Insulin-independent transporters:
Anabolic effects of insulin: GLUT1: RBCs, brain, cornea, placenta
glucose transport in skeletal muscle and GLUT2 (bidirectional): β islet cells, liver,
adipose tissue kidney, GI tract (think 2-way street)
glycogen synthesis and storage GLUT3: brain, placenta
triglyceride synthesis GLUT5 (Fructose): spermatocytes, GI tract
Na retention (kidneys) SGLT1/SGLT2 (Na -glucose cotransporters):
+
+
protein synthesis (muscles) kidney, small intestine
cellular uptake of K and amino acids Brain prefers glucose, but may use ketone bodies
+
glucagon release during starvation. RBCs utilize glucose, as they
lipolysis in adipose tissue lack mitochondria for aerobic metabolism.
Unlike glucose, insulin does not cross placenta. BRICK LIPS (insulin-independent glucose
uptake): Brain, RBCs, Intestine, Cornea, Kidney,
Liver, Islet (β) cells, Placenta, Spermatocytes.
regUlAtion Glucose is the major regulator of insulin release. insulin response with oral vs IV glucose due
to incretins (eg, glucagon-like peptide 1 [GLP-1], glucose-dependent insulinotropic polypeptide
[GIP]), which are released after meals and β cell sensitivity to glucose. Release by α 2 , by β 2
stimulation (2 = regulates insulin)
+
Glucose enters β cells ATP generated from glucose metabolism closes K channels (target
of sulfonylureas) and depolarizes β cell membrane . Voltage-gated Ca channels open
2+
2+
Ca influx and stimulation of insulin exocytosis .
Insulin
Insulin
ATP-sensitive K +
K channels close Voltage-gated
+
Ca channels
2+
open
Tyrosine ATP
phosphorylation Depolarization
ATP/ADP ratio Intracellular
Phosphoinositide-3 RAS/MAP Ca 2+
kinase pathway kinase
pathway GLUT2 Glycolysis
GLUT4 Exocytosis Insulin
Glucose Glucose Glucose of insulin
Glycogen, granules
lipid, protein
synthesis
Vesicles Cell growth,
containing DNA
GLUT4 synthesis Blood
vessel
Insulin secretion by pancreatic β cells
Insulin-dependent glucose uptake
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Adrenal steroids and congenital adrenal hyperplasias
ACTH Ketoconazole (blocks several steps in steroidogenesis)
Cholesterol (via StAR ) a
Anastrozole, letrozole, exemestane
Cholesterol desmolase
A
17α-hydroxylase 17,20-lyase
Pregnenolone 17-hydroxypregnenolone Dehydroepiandrosterone (DHEA)
3β-hydroxysteroid
dehydrogenase
17α-hydroxylase 17,20-lyase Aromatase
Progesterone 17-hydroxyprogesterone Androstenedione Estrone
B 21-hydroxylation
Aromatase
11-deoxycorticosterone 11-deoxycortisol Testosterone Estradiol
C C 11β-hydroxylation Metyrapone
5α-reductase
Corticosterone Cortisol Dihydrotestosterone
(DHT)
Aldosterone synthase Glycyrrhetinic acid
Aldosterone Cortisone Finasteride
Angiotensin II
ZONA GLOMERULOSA ZONA FASCICULATA ZONA RETICULARIS
Mineralocorticoids Glucocorticoids Androgens Estrogens, DHT
Adrenal cortex Peripheral tissue
a Rate-limiting step.
seX
enZyme deFiciency minerAlo corticoids [K ] bP cortisol hormones lAbs PresentAtion
+
17α-hydroxylase a androstenedione XY: ambiguous
genitalia,
undescended testes
XX: lacks 2° sexual
development
21-hydroxylase a renin activity Most common
17-hydroxy- Presents in infancy (salt
progesterone wasting) or childhood
(precocious puberty)
XX: virilization
11β-hydroxylase a aldosterone renin activity Presents in infancy
11-deoxycorti- (severe hypertension)
costerone or childhood
(results in (precocious puberty)
BP) XX: virilization
a All congenital adrenal enzyme deficiencies are autosomal recessive disorders and most are characterized by skin
hyperpigmentation (due to MSH production, which is coproduced and secreted with ACTH) and bilateral adrenal gland
enlargement (due to ACTH stimulation).
If deficient enzyme starts with 1, it causes hypertension; if deficient enzyme ends with 1, it causes virilization in females.
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Cortisol
soUrce Adrenal zona fasciculata. Bound to corticosteroid-binding globulin.
FUnction Appetite Cortisol is A BIG FIB.
Blood pressure: Exogenous corticosteroids can cause
Upregulates α 1 -receptors on arterioles reactivation of TB and candidiasis (blocks IL-2
sensitivity to norepinephrine and production).
epinephrine (permissive action)
At high concentrations, can bind to Stress Hypothalamus
Circadian rhythm
mineralocorticoid (aldosterone) receptors
Insulin resistance (diabetogenic) CRH
Gluconeogenesis, lipolysis, and proteolysis
( glucose utilization)
Fibroblast activity (poor wound healing, Anterior
collagen synthesis, striae) pituitary
Inflammatory and Immune responses: Endorphins
Inhibits production of leukotrienes and MSH
prostaglandins Proopiomelanocortin ACTH
Inhibits WBC adhesion neutrophilia
Blocks histamine release from mast cells
Eosinopenia, lymphopenia Cortisol
Blocks IL-2 production
Bone formation ( osteoblast activity)
Downstream cortisol
function
regUlAtion CRH (hypothalamus) stimulates ACTH release Chronic stress may induce prolonged cortisol
(pituitary) cortisol production in adrenal secretion, cortisol resistance, impaired
zona fasciculata. Excess cortisol CRH, immunocompetency, and dysregulation of
ACTH, and cortisol secretion. HPA axis.
Appetite regulation
Ghrelin Stimulates hunger (orexigenic effect) and GH release (via GH secretagog receptor). Produced by
stomach. Sleep deprivation, fasting, or Prader-Willi syndrome ghrelin production.
Ghrelin makes you hunghre and ghrow. Acts on lateral area of hypothalamus (hunger center) to
appetite.
Leptin Satiety hormone. Produced by adipose tissue. Mutation of leptin gene central obesity. (Obese
people have leptin due to adipose tissue but also appear resistant to leptin’s anorexigenic
effect.) Sleep deprivation or starvation leptin production.
Leptin keeps you thin. Acts on ventromedial area of hypothalamus (satiety center) to appetite.
Endocannabinoids Act at cannabinoid receptors in hypothalamus and nucleus accumbens, two key brain areas for the
homeostatic and hedonic control of food intake appetite.
Exogenous cannabinoids cause “the munchies.”
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Signaling pathways of endocrine hormones
cAMP FSH, LH, ACTH, TSH, CRH, hCG, ADH (V 2 - FLAT ChAMPs CHuGG
receptor), MSH, PTH, Calcitonin, Histamine
(H 2 -receptor), Glucagon, GHRH
cGMP BNP, ANP, EDRF (NO) BAD GraMPa
Think vasodilation and diuresis
IP 3 GnRH, Oxytocin, ADH (V 1 -receptor), TRH, GOAT HAG
Histamine (H 1 -receptor), Angiotensin II,
Gastrin
Intracellular receptor Progesterone, Estrogen, Testosterone, Cortisol, PET CAT on TV
Aldosterone, T 3 /T 4 , Vitamin D
Receptor tyrosine IGF-1, FGF, PDGF, EGF, TGF-β, Insulin MAP kinase pathway
kinase Get Found In the MAP
Nonreceptor tyrosine Prolactin, Immunomodulators (eg, cytokines JAK/STAT pathway
kinase IL-2, IL-6, IFN), GH, G-CSF, Erythropoietin, Think acidophils and cytokines
Thrombopoietin PIGGLET
Signaling pathways of steroid hormones
Binding to receptor Steroid hormones are lipophilic and therefore
located in nucleus H Hormone must circulate bound to specific binding
or in cytoplasm
globulins, which their solubility.
In men, sex hormone–binding globulin
Transformation of R Receptor (SHBG) lowers free testosterone
receptor to expose
DNA-binding protein gynecomastia.
In women, SHBG raises free testosterone
Binding to hirsutism.
enhancer-like H Cytoplasm
element in DNA R Gene estrogen (eg, OCPs, pregnancy) SHBG.
Intron Exon
Pre-mRNA
mRNA Nucleus
Protein
Ribosome
Response
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` endocrine—PAthology
Syndrome of Characterized by: SIADH causes include:
inappropriate Excessive free water retention Ectopic ADH (eg, small cell lung cancer)
antidiuretic Euvolemic hyponatremia with continued CNS disorders/head trauma
+
hormone secretion urinary Na excretion Pulmonary disease
Urine osmolality > serum osmolality Drugs (eg, SSRIs, carbamazepine,
Body responds to water retention with cyclophosphamide)
aldosterone and ANP and BNP Treatment: fluid restriction (first line), salt
+
urinary Na secretion normalization tablets, IV hypertonic saline, diuretics,
of extracellular fluid volume euvolemic ADH antagonists (eg, conivaptan, tolvaptan,
hyponatremia. Very low serum Na levels demeclocycline).
+
can lead to cerebral edema, seizures. Correct
slowly to prevent osmotic demyelination
syndrome (formerly called central pontine
myelinolysis).
Diabetes insipidus Characterized by intense thirst and polyuria with inability to concentrate urine due to lack of ADH
(central) or failure of response to circulating ADH (nephrogenic).
Central DI Nephrogenic DI
etiology Pituitary tumor, autoimmune, trauma, surgery, Hereditary (ADH receptor mutation), 2°
ischemic encephalopathy, idiopathic to hypercalcemia, hypokalemia, lithium,
demeclocycline (ADH antagonist)
Findings ADH Normal or ADH levels
Urine specific gravity < 1.006
Urine osmolality < 300 mOsm/kg
Serum osmolality > 290 mOsm/kg
Hyperosmotic volume contraction
WAter dePriVAtion test a > 50% in urine osmolality only after Minimal change in urine osmolality, even after
administration of ADH analog administration of ADH analog
treAtment Desmopressin HCTZ, indomethacin, amiloride
Hydration Hydration, dietary salt restriction, avoidance of
offending agent
a No water intake for 2–3 hr followed by hourly measurements of urine volume and osmolality as well as plasma Na
+
concentration and osmolality. ADH analog (desmopressin) is administered if serum osmolality > 295–300 mOsm/kg, plasma
+
Na ≥ 145 mEq/L, or urine osmolality does not rise despite a rising plasma osmolality.
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Hypopituitarism Undersecretion of pituitary hormones due to:
Nonsecreting pituitary adenoma, craniopharyngioma
Sheehan syndrome—ischemic infarct of pituitary following postpartum bleeding; pregnancy-
induced pituitary growth susceptibility to hypoperfusion. Usually presents with failure to
lactate, absent menstruation, cold intolerance
Empty sella syndrome—atrophy or compression of pituitary (which lies in the sella turcica),
often idiopathic, common in obese women; associated with idiopathic intracranial hypertension
Pituitary apoplexy—sudden hemorrhage of pituitary gland, often in the presence of an existing
pituitary adenoma. Usually presents with sudden onset severe headache, visual impairment (eg,
bitemporal hemianopia, diplopia due to CN III palsy), and features of hypopituitarism
Brain injury
Radiation
Treatment: hormone replacement therapy (corticosteroids, thyroxine, sex steroids, human growth
hormone)
Acromegaly Excess GH in adults. Typically caused by pituitary adenoma.
Findings Large tongue with deep furrows, deep voice, GH in children gigantism ( linear bone
large hands and feet, coarsening of facial growth). HF most common cause of death.
features with aging A , frontal bossing, A
diaphoresis (excessive sweating), impaired
glucose tolerance (insulin resistance),
hypertension. risk of colorectal polyps and
cancer.
diAgnosis serum IGF-1; failure to suppress serum GH
following oral glucose tolerance test; pituitary
mass seen on brain MRI. Baseline
treAtment Pituitary adenoma resection. If not cured,
treat with octreotide (somatostatin analog),
pegvisomant (GH receptor antagonist), or
dopamine agonists (eg, cabergoline).
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Hypothyroidism vs hyperthyroidism
Findings Hypothyroidism Hyperthyroidism
metAbolic Cold intolerance, sweating, weight gain Heat intolerance, sweating, weight loss
+
+
( basal metabolic rate calorigenesis), ( synthesis of Na -K ATPase basal
hyponatremia ( free water clearance) metabolic rate calorigenesis)
sKin/hAir Dry, cool skin (due to blood flow); coarse, Warm, moist skin (due to vasodilation); fine hair;
brittle hair; diffuse alopecia; brittle nails; onycholysis ( A ); pretibial myxedema in Graves
A
puffy facies and generalized nonpitting edema disease
(myxedema) due to GAGs in interstitial
spaces osmotic pressure water retention
ocUlAr Periorbital edema Ophthalmopathy in Graves disease (including
periorbital edema, exophthalmos), lid lag/
retraction ( sympathetic stimulation of
levator palpebrae superioris and superior tarsal
muscle)
gAstrointestinAl Constipation ( GI motility), appetite Hyperdefecation/diarrhea ( GI motility),
appetite
mUscUlosKeletAl Hypothyroid myopathy (proximal weakness, Thyrotoxic myopathy (proximal weakness,
CK), carpal tunnel syndrome, myoedema normal CK), osteoporosis/ fracture rate (T 3
(small lump rising on the surface of a muscle directly stimulates bone resorption)
when struck with a hammer)
reProdUctiVe Abnormal uterine bleeding, libido, infertility Abnormal uterine bleeding, gynecomastia,
libido, infertility
neUroPsychiAtric Hypoactivity, lethargy, fatigue, weakness, Hyperactivity, restlessness, anxiety, insomnia,
depressed mood, reflexes (delayed/slow fine tremors (due to β-adrenergic activity),
relaxing) reflexes (brisk)
cArdioVAscUlAr Bradycardia, dyspnea on exertion ( cardiac Tachycardia, palpitations, dyspnea, arrhythmias
output) (eg, atrial fibrillation), chest pain and systolic
HTN due to number and sensitivity of
β-adrenergic receptors, expression of cardiac
sarcolemmal ATPase and expression of
phospholamban
lAbs TSH (if 1°) TSH (if 1°)
free T 3 and T 4 free T 3 and T 4
Hypercholesterolemia (due to LDL receptor LDL, HDL, and total cholesterol
expression)
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Hypothyroidism
Hashimoto thyroiditis Most common cause of hypothyroidism in iodine-sufficient regions; an autoimmune disorder
with antithyroid peroxidase (antimicrosomal) and antithyroglobulin antibodies. Associated with
HLA-DR3, HLA-DR5, risk of non-Hodgkin lymphoma (typically of B-cell origin).
May be hyperthyroid early in course due to thyrotoxicosis during follicular rupture.
Histology: Hürthle cells A , lymphoid aggregates with germinal centers.
Findings: moderately enlarged, nontender thyroid.
Postpartum thyroiditis Self-limited thyroiditis arising up to 1 year after delivery. Presents as transient hyperthyroidism,
hypothyroidism, or hyperthyroidism followed by hypothyroidism. Majority of women are
euthyroid following resolution. Thyroid usually painless and normal in size.
Histology: lymphocytic infiltrate with occasional germinal center formation.
Congenital Severe fetal hypothyroidism due to antibody-mediated maternal hypothyroidism, thyroid
hypothyroidism dysgenesis (most common cause in US; eg, agenesis, ectopy, hypoplasia), iodine deficiency,
(cretinism) dyshormonogenetic goiter (commonly due to mutations in thyroid peroxidase).
Findings (6 P’s): Pot-bellied, Pale, Puffy-faced child B with Protruding umbilicus, Protuberant
tongue C , and Poor brain development.
Subacute Self-limited disease often following a flu-like illness (eg, viral infection).
granulomatous May be hyperthyroid early in course, followed by hypothyroidism (permanent in ~15% of cases).
thyroiditis (de Histology: granulomatous inflammation.
Quervain) Findings: ESR, jaw pain, very tender thyroid. (de Quervain is associated with pain.)
Riedel thyroiditis Thyroid replaced by fibrous tissue and inflammatory infiltrate D. Fibrosis may extend to local
structures (eg, trachea, esophagus), mimicking anaplastic carcinoma. ⁄3 of patients are hypothyroid.
1
Considered a manifestation of IgG 4 -related systemic disease (eg, autoimmune pancreatitis,
retroperitoneal fibrosis, noninfectious aortitis).
Findings: fixed, hard (rock-like), painless goiter.
Other causes Iodine deficiency (with goiter E ), goitrogens (eg, amiodarone, lithium), Wolff-Chaikoff effect
(thyroid gland downregulation in response to iodide).
A B
Before treatment After treatment
C D E
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Hyperthyroidism
Graves disease Most common cause of hyperthyroidism. Thyroid-stimulating immunoglobulin (IgG, can cause
transient neonatal hyperthyroidism; type II hypersensitivity) stimulates TSH receptors on thyroid
A
(hyperthyroidism, diffuse goiter), dermal fibroblasts (pretibial myxedema), and orbital fibroblasts
(Graves orbitopathy). Activation of T-cells lymphocytic infiltration of retroorbital space
cytokines (eg, TNF-α, IFN-γ) fibroblast secretion of hydrophilic GAGs osmotic
muscle swelling, muscle inflammation, and adipocyte count exophthalmos A . Often presents
during stress (eg, pregnancy). Associated with HLA-DR3 and HLA-B8.
Histology: tall, crowded follicular epithelial cells; scalloped colloid.
Toxic multinodular Focal patches of hyperfunctioning follicular cells distended with colloid working independently
goiter of TSH (due to TSH receptor mutations in 60% of cases). release of T 3 and T 4 . Hot nodules are
rarely malignant.
Thyroid storm Uncommon but serious complication that occurs when hyperthyroidism is incompletely treated/
untreated and then significantly worsens in the setting of acute stress such as infection, trauma,
surgery. Presents with agitation, delirium, fever, diarrhea, coma, and tachyarrhythmia (cause
of death). May see LFTs. Treat with the 4 P’s: β-blockers (eg, Propranolol), Propylthiouracil,
corticosteroids (eg, Prednisolone), Potassium iodide (Lugol iodine). Iodide load T 4 synthesis
Wolff-Chaikoff effect.
Jod-Basedow Iodine-induced hyperthyroidism. Occurs when a patient with iodine deficiency and partially
phenomenon autonomous thyroid tissue (eg, autonomous nodule) is made iodine replete. Can happen after iodine
IV contrast or amiodarone use. Opposite to Wolff-Chaikoff effect.
Causes of goiter Smooth/diffuse: Graves disease, Hashimoto thyroiditis, iodine deficiency, TSH-secreting pituitary
adenoma.
Nodular: toxic multinodular goiter, thyroid adenoma, thyroid cancer, thyroid cyst.
Thyroid adenoma Benign solitary growth of the thyroid. Most are nonfunctional (“cold”), can rarely cause
A hyperthyroidism via autonomous thyroid hormone production (“hot” or “toxic”). Most common
histology is follicular (arrows in A ); absence of capsular or vascular invasion (unlike follicular
carcinoma).
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Thyroid cancer Typically diagnosed with fine needle aspiration; treated with thyroidectomy. Complications of
surgery include hypocalcemia (due to removal of parathyroid glands), transection of recurrent
laryngeal nerve during ligation of inferior thyroid artery (leads to dysphagia and dysphonia
[hoarseness]), and injury to the external branch of the superior laryngeal nerve during ligation of
superior thyroid vascular pedicle (may lead to loss of tenor usually noticeable in professional voice
users).
Papillary carcinoma Most common, excellent prognosis. Empty-appearing nuclei with central clearing (“Orphan
Annie” eyes) A , psamMoma bodies, nuclear grooves (Papi and Moma adopted Orphan Annie).
A
risk with RET/PTC rearrangements and BRAF mutations, childhood irradiation.
Papillary carcinoma: most Prevalent, Palpable lymph nodes. Good prognosis.
Follicular carcinoma Good prognosis. Invades thyroid capsule and vasculature (unlike follicular adenoma), uniform
follicles; hematogenous spread is common. Associated with RAS mutation and PAX8-PPAR-γ
translocations.
Medullary carcinoma From parafollicular “C cells”; produces calcitonin, sheets of polygonal cells in an amyloid stroma
B (stains with Congo red). Associated with MEN 2A and 2B (RET mutations).
B
Undifferentiated/ Older patients; presents with rapidly enlarging neck mass compressive symptoms (eg, dyspnea,
anaplastic carcinoma dysphagia, hoarseness); very poor prognosis. Associated with TP53 mutation.
Diagnosing
parathyroid disease
250
2° hyperparathyroidism 1° hyperparathyroidism
2+
(vitamin D deficiency, ↓ Ca intake, (hyperplasia, adenoma,
chronic kidney disease) carcinoma)
50
PTH (pg/mL) Normal
10
1° hypoparathyroidism PTH-independent
(surgical resection, hypercalcemia
2+
autoimmune) (excess Ca intake, cancer, ↑ vitamin D)
2
4 6 8 10 12 14 16 18 20
2+
Ca (mg/dL)
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Hypoparathyroidism Due to injury to parathyroid glands or their blood supply (usually during surgery), autoimmune
A destruction, or DiGeorge syndrome. Findings: tetany, hypocalcemia, hyperphosphatemia.
Chvostek sign—tapping of facial nerve (tap the Cheek) contraction of facial muscles.
Trousseau sign—occlusion of brachial artery with BP cuff (cuff the Triceps) carpal spasm.
Pseudohypoparathyroidism type 1A—autosomal dominant, maternally transmitted mutations
(imprinted GNAS gene). GNAS1-inactivating mutation (coupled to PTH receptor) that encodes
the G s protein α subunit inactivation of adenylate cyclase when PTH binds to its receptor
end-organ resistance (kidney and bone) to PTH.
Physical findings: Albright hereditary osteodystrophy (shortened 4th/5th digits A , short stature,
round face, subcutaneous calcifications, developmental delay).
3–
2+
Labs: PTH, Ca , PO 4 .
Pseudopseudohypoparathyroidism—autosomal dominant, paternally transmitted mutations
(imprinted GNAS gene) but without end-organ resistance to PTH due to normal maternal allele
maintaining renal responsiveness to PTH.
Physical findings: same as Albright hereditary osteodystrophy.
3–
2+
Labs: normal PTH, Ca , PO 4 .
Lab values in disorder ca 2+ 3– Pth
hypocalcemia Po 4
Vitamin D deficiency
Hypoparathyroidism
2° hyperparathyroidism (CKD)
Pseudohypoparathyroidism
Hyperphosphatemia
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Hyperparathyroidism
Primary Usually due to parathyroid adenoma or Osteitis fibrosa cystica—cystic bone spaces
hyperparathyroidism hyperplasia. Hypercalcemia, hypercalciuria filled with brown fibrous tissue A (“brown
(renal stones), polyuria (thrones), tumor” consisting of osteoclasts and deposited
A
hypophosphatemia, PTH, ALP, urinary hemosiderin from hemorrhages; causes
cAMP. Most often asymptomatic. May present bone pain). Due to PTH, classically
with bone pain, weakness, constipation associated with 1° (but also seen with 2°)
(“groans”), abdominal/flank pain (kidney hyperparathyroidism.
stones, acute pancreatitis), neuropsychiatric “Stones, thrones, bones, groans, and
disturbances (“psychiatric overtones”). psychiatric overtones.”
2+
Secondary 2° hyperplasia due to Ca absorption Renal osteodystrophy—renal disease 2° and
3−
hyperparathyroidism and/or PO 4 , most often in chronic 3° hyperparathyroidism bone lesions.
kidney disease (causes hypovitaminosis D
2+
and hyperphosphatemia Ca ).
Hypocalcemia, hyperphosphatemia in
chronic kidney disease (vs hypophosphatemia
with most other causes), ALP, PTH.
Tertiary Refractory (autonomous) hyperparathyroidism
hyperparathyroidism resulting from chronic kidney disease.
2+
PTH, Ca .
2+
Familial hypocalciuric Defective G-coupled Ca -sensing receptors in multiple tissues (eg, parathyroids, kidneys). Higher
hypercalcemia than normal Ca levels required to suppress PTH. Excessive renal Ca reabsorption mild
2+
2+
hypercalcemia and hypocalciuria with normal to PTH levels.
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Diabetes mellitus
AcUte mAniFestAtions Polydipsia, polyuria, polyphagia, weight loss, DKA (type 1), hyperosmolar hyperglycemic state
(type 2).
Rarely, can be caused by unopposed secretion of GH and epinephrine. Also seen in patients on
glucocorticoid therapy (steroid diabetes).
chronic comPlicAtions Nonenzymatic glycation:
Small vessel disease (diffuse thickening of basement membrane) retinopathy (hemorrhage,
exudates, microaneurysms, vessel proliferation), glaucoma, nephropathy. Nodular
glomerulosclerosis progressive proteinuria (initially microalbuminuria; ACE inhibitors
and ARBs are renoprotective) and arteriolosclerosis (causing hypertension) chronic kidney
disease.
Large vessel atherosclerosis, CAD, peripheral vascular occlusive disease, gangrene limb loss,
cerebrovascular disease. MI most common cause of death.
Osmotic damage (sorbitol accumulation in organs with aldose reductase and or absent sorbitol
dehydrogenase):
Neuropathy (motor, sensory [glove and stocking distribution], and autonomic degeneration).
Cataracts.
diAgnosis test diAgnostic cUtoFF notes
HbA 1c ≥ 6.5% Reflects average blood glucose
over prior 3 months
Fasting plasma glucose ≥ 126 mg/dL Fasting for > 8 hours
2-hour oral glucose tolerance test ≥ 200 mg/dL 2 hours after consumption of 75 g
of glucose in water
Insulin deficiency or severe insulin insensitivity
tissue glucose ↑ glycogenolysis ↑ gluconeogenesis ↑ proteolysis ↑ lipolysis
↑
uptake
Hyperglycemia, ↓ muscle mass, ↑ plasma
glycosuria weight loss free fatty acids
↑ plasma osmolality Osmotic diuresis
Loss of water, ↑ ketogenesis,
↑ thirst + + Vomiting
Na , and K ketonemia, ketonuria
Hyperventilation, Anion gap
Hypovolemia
Kussmaul respiration metabolic acidosis
Circulation failure,
↓ tissue perfusion ↑ serum lactate
Coma/death
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Type 1 vs type 2 diabetes mellitus
Type 1 Type 2
1° deFect Autoimmune T-cell–mediated destruction of resistance to insulin, progressive pancreatic
β cells (eg, due to presence of glutamic acid β-cell failure
decarboxylase antibodies)
insUlin necessAry in treAtment Always Sometimes
Age (eXcePtions common) < 30 yr > 40 yr
AssociAtion With obesity No Yes
genetic PredisPosition Relatively weak (50% concordance in identical Relatively strong (90% concordance in identical
twins), polygenic twins), polygenic
AssociAtion With hlA system Yes, HLA-DR4 and -DR3 (4 – 3 = type 1) No
glUcose intolerAnce Severe Mild to moderate
insUlin sensitiVity High Low
KetoAcidosis Common Rare
β-cell nUmbers in the islets Variable (with amyloid deposits)
serUm insUlin leVel initially, but in advanced disease
clAssic symPtoms oF PolyUriA, Common Sometimes
PolydiPsiA, PolyPhAgiA, Weight
loss
histology Islet leukocytic infiltrate Islet amyloid polypeptide (IAPP) deposits
Diabetic ketoacidosis Insulin absent, ketones present ( complications).
Insulin noncompliance or requirements from stress (eg, infection) excess fat breakdown and
ketogenesis from free fatty acids ketone bodies (β-hydroxybutyrate > acetoacetate).
signs/symPtoms DKA is Deadly: Delirium/psychosis, Kussmaul respirations (rapid, deep breathing), Abdominal
pain/nausea/vomiting, Dehydration. Fruity breath odor (due to exhaled acetone).
–
+
lAbs Hyperglycemia, H , HCO 3 ( anion gap metabolic acidosis), urine and blood ketone levels,
+
+
leukocytosis. Normal/ serum K , but depleted intracellular K due to transcellular shift from
+
+
insulin and acidosis. Osmotic diuresis K loss in urine total body K depletion.
comPlicAtions Life-threatening mucormycosis, cerebral edema, cardiac arrhythmias, HF.
+
treAtment IV fluids, IV insulin, K (to replete intracellular stores) +/– glucose to prevent hypoglycemia.
Hyperosmolar Insulin present, ketones absent.
hyperglycemic state Profound hyperglycemia excessive osmotic diuresis dehydration and serum osmolality
HHS. Classically seen in elderly type 2 diabetics with limited ability to drink.
signs/symPtoms Thirst, polyuria, lethargy, focal neurologic deficits, seizures.
lAbs Hyperglycemia (often >600 mg/dL), serum osmolality (> 320 mOsm/kg), normal pH (no
+
+
acidosis), no ketones. Normal/ serum K , intracellular K .
comPlicAtions Can progress to coma and death if untreated.
+
treAtment IV fluids, IV insulin, and K (to replete intracellular stores).
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Cushing syndrome
etiology cortisol due to a variety of causes:
Exogenous corticosteroids ACTH bilateral adrenal atrophy. Most common cause.
Primary adrenal adenoma, hyperplasia, or carcinoma ACTH atrophy of uninvolved
adrenal gland.
ACTH-secreting pituitary adenoma (Cushing disease); paraneoplastic ACTH secretion (eg,
small cell lung cancer, bronchial carcinoids) bilateral adrenal hyperplasia. Cushing disease is
responsible for the majority of endogenous cases of Cushing syndrome.
Findings CUSHING Syndrome: Cholesterol, Urinary free cortisol, Skin changes (thinning, striae A ),
Hypertension, Immunosuppression, Neoplasm (a cause, not a finding), Growth retardation (in
children), Sugar (hyperglycemia, insulin resistance). Also, amenorrhea, moon facies B , buffalo
hump, osteoporosis, weight (truncal obesity), hirsutism.
diAgnosis Screening tests include: free cortisol on 24-hr urinalysis, late night salivary cortisol, and no
suppression with overnight low-dose dexamethasone test.
A ↑ 24-hr urine free cortisol, ↑ late night salivary cortisol, and/or
inadequate suppression on 1 mg overnight dexamethasone test
Measure serum ACTH
Suppressed Elevated
B ACTH-independent ACTH-dependent
Cushing syndrome Cushing syndrome
Exogenous glucocorticoids
or adrenal tumor High-dose dexamethasone CRH stimulation test
suppression test
(consider adrenal CT to confirm)
↑
No in ACTH
No suppression Adequate and cortisol
Ectopic ACTH suppression ↑ ACTH and cortisol
secretion Cushing disease Cushing disease Ectopic ACTH
secretion
CT of the chest/abdomen/pelvis MRI of the pituitary CT of the chest/abdomen/pelvis
Nelson syndrome Enlargement of pre-existing ACTH–secreting pituitary adenoma after bilateral adrenalectomy for
refractory Cushing disease ACTH (hyperpigmentation), mass effect (headaches, bitemporal
hemianopia).
Treatment: transsphenoidal resection, postoperative pituitary irradiation for residual tumor.
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Adrenal insufficiency Inability of adrenal glands to generate enough glucocorticoids +/− mineralocorticoids for the body’s
needs. Symptoms include weakness, fatigue, orthostatic hypotension, muscle aches, weight loss, GI
disturbances, sugar and/or salt cravings. Treatment: glucocorticoid/mineralocorticoid replacement.
Check AM or random cortisol,
or ACTH stimulation test
Metyrapone stimulation test Indeterminate ↓ AM or random
( conversion of cortisol results cortisol, or ACTH Measure random
11-deoxycortisol to cortisol) stimulation test with serum ACTH
↓ peak cortisol
↓/−/↑ ACTH ↑↑ ACTH ↑↑ ACTH
↓↓ 11-deoxycortisol ↑↑ 11-deoxycortisol ↓ 11-deoxycortisol ↓ ACTH ↑ ACTH
2°/3° adrenal Normal response 1° adrenal 2°/3° adrenal 1° adrenal
insu ciency to ↓ cortisol insu ciency insu ciency insu ciency
Primary adrenal gland function cortisol, aldosterone Primary Pigments the skin/mucosa.
insufficiency hypotension (hyponatremic volume Associated with autoimmune polyglandular
A contraction), hyperkalemia, metabolic syndromes.
acidosis, skin/mucosal hyperpigmentation Waterhouse-Friderichsen syndrome—acute
A ( melanin synthesis due to MSH, a 1° adrenal insufficiency due to adrenal
byproduct of ACTH production from POMC). hemorrhage associated with septicemia
Acute—sudden onset (eg, due to massive (usually Neisseria meningitidis), DIC,
hemorrhage). May present with shock in endotoxic shock.
acute adrenal crisis.
Chronic—Addison disease. Due to
adrenal atrophy or destruction by disease
(autoimmune destruction most common in
the Western world; TB most common in the
developing world).
Secondary adrenal Seen with pituitary ACTH production. No Secondary Spares the skin/mucosa.
insufficiency skin/mucosal hyperpigmentation (ACTH is
not elevated), no hyperkalemia (aldosterone
synthesis preserved due to functioning adrenal
gland, intact RAAS).
Tertiary adrenal Seen in patients with chronic exogenous Tertiary from Treatment.
insufficiency steroid use, precipitated by abrupt withdrawal.
Aldosterone synthesis unaffected.
Hyperaldosteronism Increased secretion of aldosterone from adrenal gland. Clinical features include hypertension,
+
or normal K , metabolic alkalosis. 1° hyperaldosteronism does not directly cause edema due
to aldosterone escape mechanism. However, certain 2° causes of hyperaldosteronism (eg, heart
failure) impair the aldosterone escape mechanism, leading to worsening of edema.
Primary Seen with adrenal adenoma (Conn syndrome) or bilateral adrenal hyperplasia. aldosterone,
hyperaldosteronism renin. Leads to treatment-resistant hypertension.
Secondary Seen in patients with renovascular hypertension, juxtaglomerular cell tumors (renin-producing),
hyperaldosteronism and edema (eg, cirrhosis, heart failure, nephrotic syndrome).
FAS1_2019_08-Endocrine.indd 349 11/7/19 4:30 PM
350 SEcTion iii EndocrinE ` endocrine—PAthology EndocrinE ` endocrine—PAthology
Neuroendocrine Heterogeneous group of neoplasms originating from neuroendocrine cells (which have traits similar
tumors to nerve cells and hormone-producing cells).
Most neoplasms occur in the GI system (eg, carcinoid, gastrinoma), pancreas (eg, insulinoma,
glucagonoma), and lungs (eg, small cell carcinoma). Also in thyroid (eg, medullary carcinoma)
and adrenals (eg, pheochromocytoma).
Neuroendocrine cells (eg, pancreatic β cells, enterochromaffin cells) share a common biologic
function through amine precursor uptake decarboxylase (APUD) despite differences in
embryologic origin, anatomic site, and secretory products (eg, chromogranin A, neuron-specific
enolase [NSE], synaptophysin, serotonin, histamine, calcitonin). Treatment: surgical resection,
somatostatin analogs.
Neuroblastoma Most common tumor of the adrenal medulla in children, usually < 4 years old. Originates from
Neural crest cells. Occurs anywhere along the sympathetic chain.
A
Most common presentation is abdominal distension and a firm, irregular mass that can cross the
midline (vs Wilms tumor, which is smooth and unilateral). Less likely to develop hypertension
than with pheochromocytoma (Neuroblastoma is Normotensive). Can also present with
opsoclonus-myoclonus syndrome (“dancing eyes-dancing feet”).
HVA and VMA (catecholamine metabolites) in urine. Homer-Wright rosettes (neuroblasts
surrounding a central lumen A ) characteristic of neuroblastoma and medulloblastoma. Bombesin
and NSE ⊕. Associated with amplification of N-myc oncogene.
Pheochromocytoma
etiology Most common tumor of the adrenal medulla in Rule of 10’s:
adults A . Derived from chromaffin cells (arise 10% malignant
A
from neural crest). 10% bilateral
May be associated with germline mutations (eg, 10% extra-adrenal (eg, bladder wall, organ of
NF-1, VHL, RET [MEN 2A, 2B]). Zuckerkandl)
10% calcify
10% kids
symPtoms Most tumors secrete epinephrine, Episodic hyperadrenergic symptoms (5 P’s):
norepinephrine, and dopamine, which can Pressure ( BP)
cause episodic hypertension. May also secrete Pain (headache)
EPO polycythemia. Perspiration
Symptoms occur in “spells”—relapse and remit. Palpitations (tachycardia)
Pallor
Findings catecholamines and metanephrines (eg, Chromogranin, synaptophysin and NSE ⊕.
homovanillic acid, vanillylmandelic acid) in
urine and plasma.
treAtment Irreversible α-antagonists (eg, Phenoxybenzamine for pheochromocytoma.
phenoxybenzamine) followed by β-blockers
prior to tumor resection. α-blockade must be
achieved before giving β-blockers to avoid a
hypertensive crisis. A before B.
FAS1_2019_08-Endocrine.indd 350 11/7/19 4:30 PM
EndocrinE ` endocrine—PAthology EndocrinE ` endocrine—PAthology SEcTion iii 351
Multiple endocrine All MEN syndromes have autosomal dominant inheritance.
neoplasias “All MEN are dominant” (or so they think).
sUbtyPe chArActeristics comments
MEN 1 Pituitary tumors (prolactin or GH)
Pancreatic endocrine tumors—Zollinger-
Ellison syndrome, insulinomas, VIPomas, Pituitary
glucagonomas (rare) Pancreas
Parathyroid adenomas
Associated with mutation of MEN1 (menin,
a tumor suppressor, chromosome 11),
angiofibromas, collagenomas, meningiomas
MEN 2A Parathyroid hyperplasia Parathyroid
Medullary thyroid carcinoma—neoplasm of
parafollicular C cells; secretes calcitonin;
prophylactic thyroidectomy required Thyroid
Pheochromocytoma (secretes catecholamines) (medullary carcinoma)
Associated with mutation in RET (codes for
receptor tyrosine kinase) Pheochromocytoma
MEN 2B Medullary thyroid carcinoma
Pheochromocytoma
A
Mucosal neuromas A (oral/intestinal
ganglioneuromatosis) Mucosal neuromas
Associated with marfanoid habitus; mutation in
RET gene
MEN 1 = 3 P’s: Pituitary, Parathyroid, and
Pancreas
MEN 2A = 2 P’s: Parathyroid and
Pheochromocytoma
MEN 2B = 1 P: Pheochromocytoma
Pancreatic islet cell tumors
Insulinoma Tumor of pancreatic β cells overproduction of insulin hypoglycemia.
May see Whipple triad: low blood glucose, symptoms of hypoglycemia (eg, lethargy, syncope,
diplopia), and resolution of symptoms after normalization of plasma glucose levels. Symptomatic
patients have blood glucose and C-peptide levels (vs exogenous insulin use). ∼ 10% of cases
associated with MEN 1 syndrome.
Treatment: surgical resection.
Glucagonoma Tumor of pancreatic α cells overproduction of glucagon.
Presents with 6 D’s: Dermatitis (necrolytic migratory erythema), Diabetes (hyperglycemia), DVT,
Declining weight, Depression, Diarrhea.
Treatment: octreotide, surgical resection.
Somatostatinoma Tumor of pancreatic δ cells overproduction of somatostatin secretion of secretin,
cholecystokinin, glucagon, insulin, gastrin, gastric inhibitory peptide (GIP).
May present with diabetes/glucose intolerance, steatorrhea, gallstones, achlorhydria.
Treatment: surgical resection; somatostatin analogs (eg, octreotide) for symptom control.
FAS1_2019_08-Endocrine.indd 351 11/7/19 4:30 PM
352 SEcTion iii EndocrinE ` endocrine—PhArmAcology EndocrinE ` endocrine—PhArmAcology
Carcinoid syndrome Carcinoid tumors arise from neuroendocrine cells most commonly in the intestine or lung. Rare
and does not occur if tumor is limited to the GI tract.
A
Prominent rosettes (arrow in A ), chromogranin A ⊕ and synaptophysin ⊕).
Neuroendocrine cells secrete 5-HT → recurrent diarrhea, wheezing, right-sided valvular heart
disease (eg, tricuspid regurgitation, pulmonic stenosis), niacin deficiency (pellagra). 5-HT
undergoes hepatic first-pass metabolism and enzymatic breakdown by MAO in the lung.
Treatment: surgical resection, somatostatin analog (eg, octreotide, telotristat) for symptom control.
Rule of thirds:
1/3 metastasize
1/3 present with 2nd malignancy
1/3 are multiple
Zollinger-Ellison Gastrin-secreting tumor (gastrinoma) of pancreas or duodenum. Acid hypersecretion causes
syndrome recurrent ulcers in duodenum and jejunum. Presents with abdominal pain (peptic ulcer disease,
distal ulcers), diarrhea (malabsorption). Positive secretin stimulation test: gastrin levels remain
elevated after administration of secretin, which normally inhibits gastrin release. May be
associated with MEN 1.
` endocrine—PhArmAcology
Diabetes mellitus All patients with diabetes mellitus should receive education on diet, exercise, blood glucose
therapy monitoring, and complication management. Treatment differs based on the type of diabetes and
glycemic control:
Type 1 DM—insulin replacement
Type 2 DM—oral agents (metformin is first line), non-insulin injectables, insulin replacement;
weight loss particularly helpful in lowering blood glucose
Gestational DM—insulin replacement if nutrition therapy and exercise alone fail
Regular (short-acting) insulin is preferred for DKA (IV), hyperkalemia (+ glucose), stress
hyperglycemia.
To Normalize Pancreatic Function ( -gliTs, -gliNs, -gliPs, -gliFs).
drUg clAss mechAnism AdVerse eFFects
Insulin preparations
Rapid acting (1-hr Bind insulin receptor (tyrosine kinase activity) Hypoglycemia, lipodystrophy, hypersensitivity
peak): Lispro, Aspart, Liver: glucose storage as glycogen reactions (rare), weight gain
Glulisine (no LAG) Muscle: glycogen, protein synthesis
Short acting (2–3 hr Fat: TG storage Lispro, aspart, glulisine
+
peak): regular Cell membrane: K uptake
Intermediate acting Regular NPH
(4–10 hr peak): NPH Plasma insulin level Detemir
Long acting (no real Glargine
peak): detemir,
glargine 0 2 4 6 8 10 12 14 16 18
Hours
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EndocrinE ` endocrine—PhArmAcology EndocrinE ` endocrine—PhArmAcology SEcTion iii 353
Diabetes mellitus therapy (continued)
drUg clAss mechAnism AdVerse eFFects
Increase insulin sensitivity
Biguanides Inhibit mGPD inhibition of hepatic GI upset, lactic acidosis (use with caution in
Metformin gluconeogenesis and the action of glucagon. renal insufficiency), vitamin B 12 deficiency.
glycolysis, peripheral glucose uptake ( insulin Weight loss (often desired).
sensitivity).
Glitazones/ Activate PPAR-γ (a nuclear receptor) insulin Weight gain, edema, HF, risk of fractures.
thiazolidinediones sensitivity and levels of adiponectin Delayed onset of action (several weeks).
“-gliTs” regulation of glucose metabolism and fatty Rosiglitazone: risk of MI, cardiovascular
Pioglitazone, acid storage. death.
rosiglitazone
Increase insulin secretion
Sulfonylureas (1st gen) DisulFIRam-like reaction (FIRst-generation
Chlorpropamide, only).
tolbutamide Rarely used.
Sulfonylureas (2nd gen) Close K channels in pancreatic B cell Hypoglycemia ( risk in renal insufficiency),
+
Glipizide, glyburide membrane cell depolarizes insulin weight gain.
2+
Meglitinides release via Ca influx.
“-gliNs”
Nateglinide,
repaglinide
Increase glucose-induced insulin secretion
GLP-1 analogs glucagon release, gastric emptying, Nausea, vomiting, pancreatitis. Weight loss
Exenatide, liraglutide glucose-dependent insulin release. (often desired).
satiety (often desired).
DPP-4 inhibitors Inhibit DPP-4 enzyme that deactivates GLP-1 Respiratory and urinary infections, weight
“-gliPs” glucagon release, gastric emptying. neutral.
Linagliptin, saxagliptin, glucose-dependent insulin release. satiety (often desired).
sitagliptin
Decrease glucose absorption
Sodium-glucose Block reabsorption of glucose in proximal Glucosuria (UTIs, vulvovaginal candidiasis),
co-transporter 2 convoluted tubule. dehydration (orthostatic hypotension),
(SGLT2) inhibitors hyperkalemia, weight loss.
“-gliFs” Use with caution in renal insufficiency
Canagliflozin, ( efficacy with GFR).
dapagliflozin,
empagliflozin
α-glucosidase Inhibit intestinal brush-border α-glucosidases GI upset, bloating.
inhibitors delayed carbohydrate hydrolysis and glucose Not recommended in renal insufficiency.
Acarbose, miglitol absorption postprandial hyperglycemia.
Others
Amylin analogs glucagon release, gastric emptying. Hypoglycemia, nausea. satiety (often desired).
Pramlintide
FAS1_2019_08-Endocrine.indd 353 11/7/19 4:30 PM
354 SEcTion iii EndocrinE ` endocrine—PhArmAcology EndocrinE ` endocrine—PhArmAcology
Thionamides Propylthiouracil, methimazole.
mechAnism Block thyroid peroxidase, inhibiting the oxidation of iodide as well as the organification and
coupling of iodine inhibition of thyroid hormone synthesis. PTU also blocks 5′-deiodinase
Peripheral conversion of T 4 to T 3 .
clinicAl Use Hyperthyroidism. PTU used in first trimester of pregnancy (due to methimazole teratogenicity);
methimazole used in second and third trimesters of pregnancy (due to risk of PTU-induced
hepatotoxicity). Not used to treat Graves ophthalmopathy (treated with corticosteroids).
AdVerse eFFects Skin rash, agranulocytosis (rare), aplastic anemia, hepatotoxicity.
Methimazole is a possible teratogen (can cause aplasia cutis).
Levothyroxine, liothyronine
mechAnism Hormone replacement for T 4 (levothyroxine) or T 3 (liothyronine).
clinicAl Use Hypothyroidism, myxedema. May be abused for weight loss. Distinguish exogenous
hyperthyroidism from endogenous hyperthyroidism by using a combination of TSH receptor
antibodies, radioactive iodine uptake, and/or measurement of thyroid blood flow on ultrasound.
AdVerse eFFects Tachycardia, heat intolerance, tremors, arrhythmias.
Hypothalamic/pituitary drugs
drUg clinicAl Use
Conivaptan, tolvaptan ADH antagonists
SIADH (block action of ADH at V 2 -receptor)
Demeclocycline ADH antagonist, a tetracycline
SIADH
Desmopressin Central DI, von Willebrand disease, sleep enuresis, hemophilia A
GH GH deficiency, Turner syndrome
Oxytocin Induction of labor (stimulates uterine contractions), control uterine hemorrhage
Somatostatin Acromegaly, carcinoid syndrome, gastrinoma, glucagonoma, esophageal varices
(octreotide)
Fludrocortisone
mechAnism Synthetic analog of aldosterone with little glucocorticoid effects.
clinicAl Use Mineralocorticoid replacement in 1° adrenal insufficiency.
AdVerse eFFects Similar to glucocorticoids; also edema, exacerbation of heart failure, hyperpigmentation.
FAS1_2019_08-Endocrine.indd 354 11/7/19 4:30 PM
EndocrinE ` endocrine—PhArmAcology EndocrinE ` endocrine—PhArmAcology SEcTion iii 355
Cinacalcet
2+
2+
mechAnism Sensitizes Ca -sensing receptor (CaSR) in parathyroid gland to circulating Ca PTH.
clinicAl Use 2° hyperparathyroidism in patients with CKD receiving hemodialysis, hypercalcemia in 1°
hyperparathyroidism (if parathyroidectomy fails), or in parathyroid carcinoma.
AdVerse eFFects Hypocalcemia.
Sevelamer
mechAnism Nonabsorbable phosphate binder that prevents phosphate absorption from the GI tract.
clinicAl Use Hyperphosphatemia in CKD.
AdVerse eFFects Hypophosphatemia, GI upset.
FAS1_2019_08-Endocrine.indd 355 11/7/19 4:30 PM
356 SEcTion ii EndocrinE ` endocrine—PhArmAcology
` `NOTES
FAS1_2019_08-Endocrine.indd 356 11/7/19 4:30 PM
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