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usmle step 1 secret study guide HIGH-YIELD PRINCIPLES PHARMACOLOGY

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201

Cholinomimetics

Drug Clinical applications Action

Direct agonists

anBethechol Postoperative and neurogenic ileus and urinary Activates Bowel and Bladder

retention smooth muscle; resistant to

AChE

Carbachol, Glaucoma Activates ciliary muscle of eye

pilocarpine (open angle), pupillary

sphincter (narrow angle);

resistant to AChE

Indirect agonists

(anticholinesterases)

Neostigmine Postoperative and neurogenic ileus and urinary . endogenous ACh

retention, myasthenia gravis, reversal of

neuromuscular junction blockade (postoperative)

Pyridostigmine Myasthenia gravis . endogenous ACh;

. strength

Edrophonium Diagnosis of myasthenia gravis (extremely short . endogenous ACh

acting)

Physostigmine Glaucoma (crosses blood-brain barrier . CNS) . endogenous ACh

and atropine overdose

Echothiophate Glaucoma . endogenous ACh

Cholinesterase Symptoms include Diarrhea, Urination, Miosis, DUMBBELSS.

inhibitor poisoning Bronchospasm, Bradycardia, Excitation of skeletal Parathion and other

muscle and CNS, Lacrimation, Sweating, and organophosphates.

Salivation (also abdominal cramping).

Antidote–atropine (muscarinic antagonist) plus

pralidoxime (chemical antagonist used to

regenerate active cholinesterase).

Cholinoreceptor blockers

Drug Organ system Application

Atropine, Eye Produce mydriasis and

homatropine, cycloplegia

tropicamide

Benztropine CNS Parkinson’s disease

Scopolamine CNS Motion sickness

Ipratropium Respiratory Asthma, COPD

Methscopolamine, Genitourinary Reduce urgency in mild

oxybutin, cystitis and reduce bladder

glycopyrrolate spasms

HIGH-YI E LD PRINCIPLES PHARMACOLOGY

202

PHARMACOLOGY-AUTONOMIC DRUGS (continued)

Atropine Muscarinic antagonist.

Organ system

Eye . pupil dilation, cycloplegia. Blocks SLUD:

Airway . secretions. Salivation

Stomach . acid secretion. Lacrimation

Gut . motility. Urination

Bladder . urgency in cystitis. Defecation

Toxicity . body temperature; rapid pulse; dry mouth; dry, Side effects:

flushed skin; cycloplegia; constipation; Hot as a hare

disorientation. Dry as a bone

Can cause acute angle-closure glaucoma in Red as a beet

elderly, urinary retention in men with Blind as a bat

prostatic hypertrophy, and hyperthermia Mad as a hatter

in infants.

Hexamethonium

Mechanism Nicotinic ACh receptor antagonist.

Clinical use Ganglionic blocker. Used in experimental models to prevent vagal reflex responses to

changes in blood pressure–e.g., prevents reflex bradycardia caused by NE.

PHARMACOLOGY HIGH-YI E LD PRINCIPLES

Sympathomimetics

Drug Mechanism/selectivity Applications

Catecholamines

Epinephrine Direct general agonist (a1, a2, ß1, ß2) Anaphylaxis, glaucoma (open

angle), asthma, hypotension

NE a1, a2, ß1 Hypotension (but . renal

perfusion)

Isoproterenol ß1 = ß2 AV block (rare)

Dopamine D1 = D2 > ß > a Shock (. renal perfusion),

heart failure

Dobutamine ß1 > ß2 Shock, heart failure

Other

Amphetamine Indirect general agonist, releases stored Narcolepsy, obesity, attention

catecholamines deficit disorder

Ephedrine Indirect general agonist, releases stored Nasal decongestion, urinary

catecholamines incontinence, hypotension

Phenylephrine a1 > a2 Pupil dilator, vasoconstriction,

nasal decongestion

Albuterol, ß2 > ß1 Asthma

terbutaline

Cocaine Indirect general agonist, uptake inhibitor Causes vasoconstriction and

local anesthesia

Clonidine, Centrally acting a-agonist, . central Hypertension, especially with

a-methyldopa adrenergic outflow renal disease (no . in blood

flow to kidney)

HIGH-YI E LD PRINCIPLES PHARMACOLOGY

203

Heart rate Blood pressure

Systolic

Mean

Diastolic

Norepinephrine (a > ß)

(Reflex bradycardia)

Epinephrine (nonselective) Isoproterenol (ß > a)

150

100

50

100

50

Pulse

pressure

(Adapted, with permission, from Katzung BG, Trevor AJ. Pharmacology: Examination & Board Review, 5th ed. Stamford, CT: Appleton &

Lange, 1998:72.)

204

PHARMACOLOGY-AUTONOMIC DRUGS (continued)

a-blockers

Drugs Application Toxicity

Nonselective

Phenoxybenzamine Pheochromocytoma Orthostatic hypotension,

(irreversible) reflex tachycardia

and phentolamine

(reversible)

a1 selective

Prazosin, terazosin, Hypertension, urinary retention in BPH 1st-dose orthostatic hypotension,

doxazosin dizziness, headache

a2 selective

Mirtazapine Depression Sedation, . serum cholesterol, . appetite

Shown above are the effects of an a-blocker (e.g., phentolamine) on blood pressure responses to epinephrine and

phenylephrine. The epinephrine response exhibits reversal of the mean blood pressure change, from a net

increase (the a response) to a net decrease (the ß2 response). The response to phenylephrine is suppressed but

not reversed because phenylephrine is a “pure” a-agonist without ß action.

PHARMACOLOGY HIGH-YI E LD PRINCIPLES

(Adapted, with permission, from Katzung BG, Trevor AJ. Pharmacology: Examination & Board Review, 5th ed. Stamford,

CT: Appleton & Lange, 1998:80.)

Epi (large dose) Epi (large dose)

Before alpha blockade After alpha blockade

Phenylephrine Phenylephrine

Blood pressure Blood pressure

Net pressor effect Net depressor effect

Net pressor effect Suppression of pressor effect

205

ß-blockers Propranolol, metoprolol, atenolol, nadolol, timolol, pindolol, esmolol, labetalol.

Application Effect

Hypertension . cardiac output, . renin secretion

Angina pectoris . heart rate and contractility, resulting in . O2

consumption

MI ß-blockers . mortality

SVT (propranolol, . AV conduction velocity

esmolol)

CHF Slows progression of chronic failure

Glaucoma (timolol) . secretion of aqueous humor

Toxicity Impotence, exacerbation of asthma, cardiovascular

adverse effects (bradycardia, AV block, CHF),

CNS adverse effects (sedation, sleep alterations);

use with caution in diabetics

Selectivity Nonselective (ß1 = ß2)–propranolol, timolol, nadolol,

pindolol (partial agonist), and labetalol (partial

agonist)

ß1 selective (ß1 > ß2)–Acebutolol (partial agonist), A BEAM of ß1 blockers.

Betaxolol, Esmolol (short acting), Atenolol,

Metoprolol

Glaucoma drugs

Drug Mechanism Side effects

a-agonists

Epinephrine . outflow of aqueous humor Mydriasis, stinging; do not use

in closed-angle glaucoma

Brimonidine . aqueous humor synthesis No pupillary or vision changes

ß-blockers

Timolol, betaxolol, . aqueous humor secretion No pupillary or vision changes

carteolol

Diuretics

Acetazolamide . aqueous humor secretion due to No pupillary or vision changes

. HCO3

– (via inhibition of carbonic

anhydrase)

Cholinomimetics

Pilocarpine, . outflow of aqueous humor; contract ciliary Miosis, cyclospasm

carbachol, muscle and open trabecular meshwork

physostigmine,

echothiophate

Prostaglandin

Latanoprost . outflow of aqueous humor Darkens color of iris (browning)

(PGF2a)

HIGH-YI E LD PRINCIPLES PHARMACOLOGY

206

PHARMACOLOGY-TOXIC ITIES AND S IDE EFFECTS

Specific antidotes Toxin Antidote/treatment

1. Acetaminophen 1. N-acetylcysteine

2. Salicylates 2. Alkalinize urine, dialysis

3. Anticholinesterases, organophosphates 3. Atropine, pralidoxime

4. Antimuscarinic, anticholinergic agents 4. Physostigmine salicylate

5. ß-blockers 5. Glucagon

6. Digitalis 6. Stop dig, normalize K+,

lidocaine, anti-dig Fab

fragments, Mg2+

7.Iron 7.Deferoxamine

8. Lead 8. CaEDTA, dimercaprol,

succimer, penicillamine

9. Arsenic, mercury, gold 9. Dimercaprol (BAL),

succimer

10. Copper, arsenic, gold 10. Penicillamine

11. Cyanide 11. Nitrite, hydroxocobalamin,

thiosulfate

12. Methemoglobin 12. Methylene blue

13. Carbon monoxide 13. 100% O2, hyperbaric O2

14. Methanol, ethylene glycol (antifreeze) 14. Ethanol, dialysis, fomepizole

15. Opioids 15. Naloxone/naltrexone

16. Benzodiazepines 16. Flumazenil

17. TCAs 17. NaHCO3 (nonspecific)

18. Heparin 18. Protamine

19. Warfarin 19. Vitamin K, fresh frozen

plasma

20. tPA, streptokinase 20. Aminocaproic acid

Lead poisoning Lead Lines on gingivae and on epiphyses of long LEAD.

bones on x-ray. High risk in houses with

Encephalopathy and Erythrocyte basophilic chipped paint.

stippling.

Abdominal colic and sideroblastic Anemia.

Drops–wrist and foot drop. Dimercaprol and It “sucks” to be a kid who eats

EDTA 1st line of treatment. Succimer for kids. lead.

Urine pH and drug Weak acids (phenobarbital, methotrexate, aspirin) alkalinize urine with bicarbonate

elimination to . clearance.

Weak bases (amphetamines) acidify urine to . clearance (give NH4Cl).

PHARMACOLOGY HIGH-YI E LD PRINCIPLES

207

Drug reactions

Drug reaction by Causal agent

system

Cardiovascular

Atropine-like side Tricyclics

effects

Cardiac toxicity Doxorubicin (Adriamycin), daunorubicin

Coronary vasospasm Cocaine

Cutaneous flushing Niacin, Ca2+ channel blockers, adenosine, vancomycin

Torsades de pointes Class III (sotalol), class IA (quinidine) antiarrhythmics, cisapride

Hematologic

Agranulocytosis Clozapine, carbamazepine, colchicine

Aplastic anemia Chloramphenicol, benzene, NSAIDs

Gray baby syndrome Chloramphenicol

Hemolysis in G6PD- Sulfonamides, isoniazid (INH), aspirin, ibuprofen, primaquine, nitrofurantoin

deficient patients

Thrombotic OCPs (e.g., estrogens and progestins)

complications

Respiratory

Cough ACE inhibitors (losartan–no cough)

Pulmonary fibrosis Bleomycin, amiodarone, busulfan

GI

Acute cholestatic Macrolides

hepatitis

Focal to massive Halothane, valproic acid, acetaminophen, Amanita phalloides

hepatic necrosis

Hepatitis INH

Pseudomembranous Clindamycin, ampicillin

colitis

Reproductive/endocrine

Adrenocortical Glucocorticoid withdrawal (HPA suppression)

insufficiency

Gynecomastia Spironolactone, Digitalis, Cimetidine, chronic Alcohol use, estrogens, Ketoconazole

(Some Drugs Create Awesome Knockers)

Hot flashes Tamoxifen

Musculoskeletal/

connective tissue

Gingival hyperplasia Phenytoin

Osteoporosis Corticosteroids, heparin

Photosensitivity Sulfonamides, Amiodarone, Tetracycline (SAT for a photo)

SLE-like syndrome Hydralazine, INH, Procainamide, Phenytoin (it’s not HIPP to have lupus)

Tendonitis, tendon Fluoroquinolones

rupture, and

cartilage damage

(kids)

Renal

Fanconi’s syndrome Expired tetracycline

Interstitial nephritis Methicillin

Hemorrhagic cystitis Cyclophosphamide, ifosfamide

HIGH-YI E LD PRINCIPLES PHARMACOLOGY

208

PHARMACOLOGY-TOXIC ITIES AND S IDE EFFECTS (continued)

Drug reactions (continued)

Neurologic

Cinchonism Quinidine, quinine

Diabetes insipidus Lithium, demeclocycline

Seizures Bupropion, imipenem/cilastatin

Tardive dyskinesia Antipsychotics

Multiorgan

Disulfiram-like Metronidazole, certain cephalosporins, procarbazine, sulfonylureas

reaction

Nephrotoxicity/ Polymyxins

neurotoxicity

Nephrotoxicity/ Aminoglycosides, loop diuretics, cisplatin

ototoxicity

P-450 interactions

Inducers Inhibitors Inducers:

Quinidine Isoniazid Queen Barb takes Phen-phen

Barbiturates Sulfonamides and Refuses Greasy Carbs.

Phenytoin Cimetidine

Rifampin Ketoconazole Inhibitors:

Griseofulvin Erythromycin Inhibitors Stop Cyber-Kids

Carbamazepine Grapefruit juice from Eating GrapefruitS.

St. John’s wort

Alcohol toxicity

PHARMACOLOGY HIGH-YI E LD PRINCIPLES

Ethylene

glycol

Alcohol

dehydrogenase

Oxalic acid Acidosis,

nephrotoxicity

Methanol Alcohol

dehydrogenase

Formaldehyde

and formic acid

Severe acidosis,

retinal damage

Ethanol Alcohol

dehydrogenase

Acetaldehyde Nausea, vomiting,

headache,

hypotension

Acetaldehyde

dehydrogenase

Acetic acid

INHIBITED BY

DISULFIRAM

COMPETITIVE

SUBSTRATES

FOR ADH

209

PHARMACOLOGY-MISCELLANEOUS

Herbal agents

Agent Clinical uses Toxicities

Echinacea Common cold GI distress, dizziness, and headache

Ephedra As for ephedrine CNS and cardiovascular stimulation; arrhythmias,

stroke, and seizures at high doses

Feverfew Migraine GI distress, mouth ulcers, antiplatelet actions

Ginkgo Intermittent claudication GI distress, anxiety, insomnia, headache,

antiplatelet actions

Kava Chronic anxiety GI distress, sedation, ataxia, hepatotoxicity,

phototoxicity, dermatotoxicity

Milk thistle Viral hepatitis Loose stools

Saw palmetto Benign prostatic hyperplasia GI distress, . libido, hypertension

St. John’s wort Mild to moderate depression GI distress and phototoxicity; serotonin syndrome

with SSRIs; inhibits P-450 system

Dehydroepi- Symptomatic improvement in Androgenization (premenopausal women),

androsterone females with SLE or AIDS estrogenic effects (postmenopausal),

feminization (young men)

Melatonin Jet lag, insomnia Sedation, suppresses midcycle LH,

hypoprolactinemia

Drug name

Ending Category Example

-afil Erectile dysfunction Sildenafil

-ane Inhalational general anesthetic Halothane

-azepam Benzodiazepine Diazepam

-azine Phenothiazine (neuroleptic, antiemetic) Chlorpromazine

-azole Antifungal Ketoconazole

-barbital Barbiturate Phenobarbital

-caine Local anesthetic Lidocaine

-cillin Penicillin Methicillin

-cycline Antibiotic, protein synthesis inhibitor Tetracycline

-ipramine TCA Imipramine

-navir Protease inhibitor Saquinavir

-olol ß-antagonist Propranolol

-operidol Butyrophenone (neuroleptic) Haloperidol

-oxin Cardiac glycoside (inotropic agent) Digoxin

-phylline Methylxanthine Theophylline

-pril ACE inhibitor Captopril

-terol ß2 agonist Albuterol

-tidine H2 antagonist Cimetidine

-triptyline TCA Amitriptyline

-tropin Pituitary hormone Somatotropin

-zosin a1 antagonist Prazosin

HIGH-YI E LD PRINCIPLES PHARMACOLOGY

(Adapted, with permission, from Katzung BG, Trevor AJ. USMLE Road Map: Pharmacology, 1st ed. New York: McGraw-Hill, 2003.)

210 PHARMACOLOGY HIGH-YI E LD PRINCIPLES

NOTES

Approaching the Organ

Systems

Cardiovascular

Endocrine

Gastrointestinal

Hematology and

Oncology

Musculoskeletal and

Connective Tissue

Neurology and

Psychiatry

Renal

Reproductive

Respiratory

S E C T I O N I I I

High-Yield

Organ Systems

211

212

APPROACHING THE ORGAN SYSTEMS

In this section, we have divided the High-Yield Facts into the major Organ Systems. Within each Organ

System are several subsections, including Anatomy, Physiology, Pathology, and Pharmacology. As you

progress through each Organ System, refer back to information in the previous subsections to organize

these basic science subsections into a “vertical” framework for learning. Below is some general advice for

studying the organ systems by these subsections.

Anatomy

Several topics fall under this heading, including embryology, gross anatomy, histology, and neuroanatomy.

Do not memorize all the small details; however, do not ignore anatomy altogether. Review

what you have already learned and what you wish you had learned. Many questions require two steps.

The first step is to identify a structure on anatomic cross section, electron micrograph, or photomicrograph.

The second step may require an understanding of the clinical significance of the structure.

When studying, stress clinically important material. For example, be familiar with gross anatomy related

to specific diseases (e.g., Pancoast’s tumor, Horner’s syndrome), traumatic injuries (e.g., fractures, sensory

and motor nerve deficits), procedures (e.g., lumbar puncture), and common surgeries (e.g., cholecystectomy).

There are also many questions on the exam involving x-rays, CT scans, and neuro MRI scans.

Many students suggest browsing through a general radiology atlas, pathology atlas, and histology atlas. Focus

on learning basic anatomy at key levels in the body (e.g., sagittal brain MRI; axial CT of midthorax,

abdomen, and pelvis). Basic neuroanatomy (especially pathways, blood supply, and functional anatomy)

also has good yield. Use this as an opportunity to learn associated neuropathology and neurophysiology.

Basic embryology (especially congenital malformations) is worth reviewing as well.

Physiology

The portion of the examination dealing with physiology is broad and concept oriented and thus does not

lend itself as well to fact-based review. Diagrams are often the best study aids, especially given the increasing

number of questions requiring the interpretation of diagrams. Learn to apply basic physiologic

relationships in a variety of ways (e.g., Fick equation, clearance equations). You are seldom asked to perform

complex calculations. Hormones are the focus of many questions. Learn their sites of production

and action as well as their regulatory mechanisms.

A large portion of the physiology tested on the USMLE Step 1 is now clinically relevant and involves understanding

physiologic changes associated with pathologic processes (e.g., changes in pulmonary function

with COPD). Thus, it is worthwhile to review the physiologic changes that are found with common

pathologies of the major organ systems (e.g., heart, lungs, kidneys, GI tract) and endocrine glands.

Pathology

Questions dealing with this discipline are difficult to prepare for because of the sheer volume of material.

Review the basic principles and hallmark characteristics of the key diseases. Given the increasingly clinical

orientation of Step 1, it is no longer enough to know only the “trigger word” associations of certain

diseases (e.g., café-au-lait macules and neurofibromatosis); you must also know the clinical descriptions

of these findings.

213

Given the clinical slant of the USMLE Step 1, it is also important to review the classic presenting signs

and symptoms of diseases as well as their associated laboratory findings. Delve into the signs, symptoms,

and pathophysiology of the major diseases having a high prevalence in the United States (e.g., alcoholism,

diabetes, hypertension, heart failure, ischemic heart disease, infectious disease). Be prepared to

think one step beyond the simple diagnosis to treatment or complications.

The examination includes a number of color photomicrographs and photographs of gross specimens that

are presented in the setting of a brief clinical history. However, read the question and the choices carefully

before looking at the illustration, because the history will help you identify the pathologic process.

Flip through an illustrated pathology textbook, color atlases, and appropriate Web sites in order to look at

the pictures in the days before the exam. Pay attention to potential clues such as age, sex, ethnicity, occupation,

recent activities and exposures, and specialized lab tests.

Pharmacology

Preparation for questions on pharmacology is straightforward. Memorizing all the key drugs and their

characteristics (e.g., mechanisms, clinical use, and important side effects) is high yield. Focus on understanding

the prototype drugs in each class. Avoid memorizing obscure derivatives. Learn the “classic”

and distinguishing toxicities of the major drugs. Do not bother with drug dosages or trade names. Reviewing

associated biochemistry, physiology, and microbiology can be useful while studying pharmacology.

There is a strong emphasis on ANS, CNS, antimicrobial, and cardiovascular agents as well as on

NSAIDs. Much of the material is clinically relevant. Newer drugs on the market are also fair game.

High-Yield Clinical

Vignettes

Anatomy

Physiology

Pathology

Pharmacology

H I G H -Y I E L D S Y S T E M S

Cardiovascular

215

“As for me, except for an occasional heart attack, I feel as young as I ever did.”

–Robert Benchley

“Hearts will never be practical until they are made unbreakable.”

–The Wizard of Oz

216

CARDIOVASCULAR-HIGH-YIELD CLINICAL VIGNETTES

Pregnant woman in 3rd trimester What is the diagnosis? Compression of the IVC.

has normal blood pressure when

standing and sitting. When supine,

blood pressure drops to 90/50.

35-year-old man has high blood What is the diagnosis? Coarctation of the aorta.

pressure in his arms and low

pressure in his legs.

5-year-old boy presents with What is the diagnosis? ASD.

systolic murmur and wide,

fixed split S2.

During a game, a young What is the most likely Hypertrophic cardiomyopathy.

football player collapses and type of cardiac disease?

dies immediately.

Patient has a stroke after What caused the infarct? Fat emboli.

incurring multiple long bone

fractures in trauma stemming

from a motor vehicle accident.

Elderly woman presents with a What is the diagnosis? Temporal arteritis.

headache and jaw pain. Labs

show elevated ESR.

80-year-old man presents with a What is the most likely Aortic stenosis.

systolic crescendo-decrescendo cause?

murmur.

Man starts a medication for What drug was it? Niacin.

hyperlipidemia. He then

develops a rash, pruritus, and

GI upset.

Patient develops a cough and What is a good Losartan, an angiotensin II

must discontinue captopril. replacement drug, and receptor antagonist, does not .

why doesn’t it have the bradykinin as captopril does.

same side effects?

CARDIOVASCULAR HIGH-YI E LD SYSTEMS

217

CARDIOVASCULAR-ANATOMY

Carotid sheath 3 structures inside: VAN.

1. Internal jugular Vein (lateral)

2. Common carotid Artery (medial)

3. Vagus Nerve (posterior)

Coronary artery In the majority of cases, the SA

anatomy and AV nodes are supplied

by the RCA. 80% of the

time, the RCA supplies

the inferior portion of the

left ventricle via the PD

artery (= right dominant).

Coronary artery occlusion

occurs most commonly

in the LAD, which supplies

the anterior interventricular

septum.

Coronary arteries fill during

diastole.

The most posterior part of the

heart is the left atrium;

enlargement can cause

dysphagia.

HIGH-YI E LD SYSTEMS CARDIOVASCULAR

Acute marginal artery

Left main coronary artery (LCA)

Circumflex artery (CFX)

Left anterior

descending

artery (LAD)

Posterior descending artery (PD)

Right coronary

artery (RCA)

(Adapted, with permission, from Ganong WF. Review of Medical Physiology,

19th ed. Stamford, CT: Appleton & Lange, 1999:592.)

218

CARDIOVASCULAR-PHYSIOLOGY

Cardiac output (CO) Cardiac output (CO) = (stroke volume) × (heart rate). During exercise, CO .

Fick principle: initially as a result of an

CO = rate of O2 consumption . in SV. After prolonged

arterial O2 content – venous O2 content

exercise, CO . as a result

of an . in HR.

If HR is too high, diastolic

filling is incomplete and CO

. (e.g., ventricular

tachycardia).

MAP = 1/3 systolic + 2/3 diastolic.

Pulse pressure = systolic – diastolic.

Pulse pressure ˜ stroke volume.

SV =CO = EDV – ESV

HR

Cardiac output Stroke Volume affected by Contractility, Afterload, SV CAP.

variables and Preload. . SV when . preload, . afterload,

or . contractility.

Contractility (and SV) . with: SV . in anxiety, exercise,

1. Catecholamines (. activity of Ca2+pump and pregnancy.

in sarcoplasmic reticulum) A failing heart has . SV.

2. . intracellular calcium Myocardial O2 demand is . by:

3. . extracellular sodium 1. . afterload (.

4. Digitalis (. intracellular Na+, resulting diastolic BP)

in . Ca2+) 2.. contractility

Contractility (and SV) . with: 3. . heart rate

1. ß1 blockade 4. . heart size (. wall

2. Heart failure tension)

3. Acidosis

4. Hypoxia/hypercapnea

5. Ca2+ channel blockers

Preload and Preload = ventricular EDV. Preload . with exercise

afterload Afterload = systolic arterial pressure (slightly), . blood volume

(proportional to peripheral resistance). (overtransfusion), and

Venous dilators (e.g., nitroglycerin) . preload. excitement (sympathetics).

Vasodilators (e.g., hydralazine) . afterload. Preload pumps up the heart.

CARDIOVASCULAR HIGH-YI E LD SYSTEMS

Mean arterial

= (cardiac) × (total peripheral) pressure output resistance

219

Starling curve Force of contraction is proportional to initial length of cardiac muscle fiber (preload).

Ejection fraction EF = SV = EDV – ESV

EDV EDV

EF is an index of ventricular contractility.

EF is normally = 55%.

Resistance, .P = Q × R

pressure, flow Similar to Ohm’s law: V = IR.

Resistance =

driving pressure (.P)

=

8. (viscosity) × length Resistance is directly

flow (Q) p r4 proportional to viscosity

Viscosity depends mostly on hematocrit. and inversely proportional

Viscosity . in: to the radius to the 4th

1. Polycythemia power.

2. Hyperproteinemic states (e.g., multiple myeloma)

3. Hereditary spherocytosis

Cardiac and vascular function curves

HIGH-YI E LD SYSTEMS CARDIOVASCULAR

Sympathetic

Exercise nerve impulses

Normal

CHF + digitalis

CHF

Ventricular EDV

Preload

CO or stroke volume

CONTRACTILE STATE OF MYOCARDIUM

Circulating

catecholamines

Digitalis

Sympathetic

stimulation

Pharmacologic

depressants

Loss of

myocardium (MI)

+ –

. blood volume CO or venous return

. blood volume

(+) inotropy

Right atrial pressure

or EDV

CO

(-) inotropy

Venous return

220

CARDIOVASCULAR-PHYSIOLOGY (continued)

Cardiac cycle Phases:

1. Isovolumetric contraction–period

between mitral valve closure and

aortic valve opening; period of

highest O2 consumption

2. Systolic ejection–period between

aortic valve opening and closing

3. Isovolumetric relaxation–period

between aortic valve closing and

mitral valve opening

4. Rapid filling–period just after

mitral valve opening

5. Slow filling–period just before

mitral valve closure

Sounds:

S1–mitral and tricuspid valve closure.

S2–aortic and pulmonary valve closure.

S3–at end of rapid ventricular filling.

S4–high atrial pressure/stiff ventricle.

S3 is associated with dilated CHF.

S4 (“atrial kick”) is associated with a

hypertrophic ventricle.

a wave–atrial contraction.

c wave–RV contraction (tricuspid valve

bulging into atrium).

v wave– . atrial pressure due to

filling against closed tricuspid valve.

Jugular venous distention is seen in

right heart failure.

S2 splitting: aortic valve closes before

pulmonic; inspiration . this

difference.

CARDIOVASCULAR HIGH-YI E LD SYSTEMS

Ejection

Ventricular volume (mL)

Ventricular filling

Isovolumetric contraction

Isovolumetric relaxation

Pressure (mmHg)

140

120

100

80

60

40

20

0

40 85 130

1

2

3

4 & 5

Aortic valve

closes

Aortic valve

opens

Mitral valve

closes

Mitral valve

opens

Stroke volume

(EDV-ESV)

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8

Time (sec)

P

P

Q

R

S

T ECG

a c

v

Jugular

venous

pulse

Ventricular

volume

S4 S1 S2

S3

Heart

sounds

Mitral

valve

closes Left atrial pressure

Mitral valve opens

Left ventricular

pressure

Aortic

pressure

Aortic valve closes

Dicrotic notch

Aortic

valve

opens

Pressure (mmHg)

Atrial

systole

Isovolumetric

contraction

Rapid ejection

Reduced

ejection

Isovolumetric

relaxation

Rapid

ventricular filling

Reduced

ventricular

filling

120

100

80

60

40

20

0

x y

(Adapted, with permission, from Ganong WF. Review of Medical Physiology, 22nd ed. McGraw-Hill, 2005.)

A2 P2

Normal splitting: | | |

S1 S2

Paradoxical splitting (associated with

aortic stenosis): P2 A2

Expiration | | |

P2 A2

Inspiration | | |

S1 S2

} }

221

Pressure-volume relationship

Cardiac myocyte Cardiac muscle contraction is dependent on extracellular calcium, which enters the

physiology cells during plateau of action potential and stimulates calcium release from the cardiac

muscle sarcoplasmic reticulum (calcium-induced calcium release).

In contrast to skeletal muscle:

1. Cardiac muscle action potential has a plateau, which is due to Ca2+ influx

2. Cardiac nodal cells spontaneously depolarize, resulting in automaticity

3. Cardiac myocytes are electrically coupled to each other by gap junctions

Myocardial action potential

Occurs in atrial and ventricular myocytes and Purkinje fibers.

Phase 0 = rapid upstroke–voltage-gated Na+ channels open.

Phase 1 = initial repolarization–inactivation of voltage-gated Na+ channels. Voltagegated

K+ channels begin to open.

Phase 2 = plateau–Ca2+ influx through voltage-gated Ca2+ channels balances K+ efflux.

Ca2+ influx triggers another Ca2+ release from sarcoplasmic reticulum and myocyte

contraction.

Phase 3 = rapid repolarization–massive K+ efflux due to opening of voltage-gated slow

K+ channels and closure of voltage-gated Ca2+ channels.

Phase 4 = resting potential–high K+ permeability through K+ channels.

HIGH-YI E LD SYSTEMS CARDIOVASCULAR

Phase 3 (IK+)

Phase 2 (ICa2+ & IK+)

Phase 4 (dominated by IK+)

Effective refractory period (ERP)

Phase 0

INa

0 mV

100 msec

-85 mV

Outside

Membrane

Inside

Na+ Ca2+

Na+ Na+

ATP

Ca2+

Exchanger

K+

Pump

K+ Na+ Ca2+

“Leak” currents

K+

Channel currents

Phase 1

. afterload

EDV . preload

Volume

ESV •

Pressure

CARDIOVASCULAR-PHYSIOLOGY (continued)

Pacemaker action Occurs in the SA and AV nodes. Key differences from the ventricular action potential

potential include:

Phase 0 = upstroke–opening of voltage-gated Ca2+ channels. These cells lack fast

voltage-gated Na+ channels. Results in a slow conduction velocity that is used by the

AV node to prolong transmission from the atria to ventricles.

Phase 2 = plateau is absent.

Phase 4 = slow diastolic depolarization–membrane potential spontaneously depolarizes

as Na+ conductance . (If different from INa above). Accounts for automaticity of SA

and AV nodes. The slope of phase 4 in the SA node determines heart rate. ACh . and

catecholamines . the rate of diastolic depolarization, decreasing or increasing

heart rate, respectively.

222 CARDIOVASCULAR HIGH-YI E LD SYSTEMS

0

-20

-40

-60

-80

100 msec

Millivolts

Phase 0

ICa2+

If Na+

Phase 3

IK

+

Phase 4

(Adapted, with permission, from Ganong WF et al. Review of Medical Physiology, 22nd ed. New York: McGraw-

Hill, 2005.)

223

Electrocardiogram P wave–atrial depolarization.

PR segment–conduction delay through AV node (normally < 200 msec).

QRS complex–ventricular depolarization (normally < 120 msec).

QT interval–mechanical contraction of the ventricles.

T wave–ventricular repolarization.

Atrial repolarization is masked by QRS complex.

ST segment–isoelectric, ventricles depolarized.

U wave–caused by hypokalemia.

Wolff-Parkinson-White syndrome

Accessory conduction pathway from atria to ventricle (bundle of Kent), bypassing AV

node. As a result, ventricles begin to partially depolarize earlier, giving rise to

characteristic delta wave on ECG. May result in reentry current leading to

supraventricular tachycardia.

HIGH-YI E LD SYSTEMS CARDIOVASCULAR

(Adapted, with permission, from Ganong WF. Review of Medical Physiology, 22nd ed. New York: McGraw-Hill, 2005.)

SA node “pacemaker” inherent dominance with slow phase of upstroke

AV node – 100-msec delay – atrioventricular delay

d wave

Superior

vena cava

Sinoatrial

node

Internodal

pathways

Atrioventricular

node

Right bundle branch

Purkinje system

Left posterior fascicle

Aorta

SA node

Atrial muscle

AV node

Common bundle

Bundle branches

Purkinje fibers

Ventricular

muscle

LAF

Time (s)

1.0

0.5

0

-0.5

0 0.2 0.4 0.6

R

P T

S

Q

U

Isoelectric

line

ST

segment

PR

interval

QT

interval

Potential (mV)

Action

potential

Time (s)

ECG

QRS

P T

0.2 0.4 0.6

Bundle of His

QRS complex

224

CARDIOVASCULAR-PHYSIOLOGY (continued)

ECG tracings

Atrial fibrillation Chaotic and erratic baseline (irregularly irregular) with no discrete P waves in between

irregularly spaced QRS complexes.

Atrial flutter A rapid succession of identical, back-to-back atrial depolarization waves. The identical

appearance accounts for the “sawtooth” appearance of the flutter waves.

AV block

1st degree The PR interval is prolonged (> 200 msec). Asymptomatic.

2nd degree

Mobitz type I Progressive lengthening of the PR interval until a beat is “dropped” (a P wave not

(Wenckebach) followed by a QRS complex). Usually asymptomatic.

CARDIOVASCULAR HIGH-YI E LD SYSTEMS

Note progressive increase in PR length before dropped beat

Prolonged PR interval

225

ECG tracings (continued)

Mobitz type II Dropped beats that are not preceded by a change in the length of the PR interval (as in

type I). These abrupt, nonconducted P waves result in a pathologic condition. It is often

found as 2:1 block, where there are 2 P waves to 1 QRS response. May progress to 3rddegree

block.

3rd degree The atria and ventricles beat independently of each other. Both P waves and QRS

(complete) complexes are present, although the P waves bear no relation to the QRS complexes.

The atrial rate is faster than the ventricular rate. Usually treat with pacemaker.

Ventricular A completely erratic rhythm with no identifiable waves. Fatal arrhythmia without

fibrillation immediate CPR and defibrillation.

HIGH-YI E LD SYSTEMS CARDIOVASCULAR

No QRS following P wave, normal PR intervals

P on T wave P wave on ST-T complex

(Adapted, with permission, from Hurst JW. Introduction to Electrocardiography. New York: McGraw-Hill, 2001.)

226

CARDIOVASCULAR-PHYSIOLOGY (continued)

Control of mean arterial pressure

Baroreceptors and chemoreceptors

Receptors:

1. Aortic arch transmits via vagus nerve to medulla (responds only to . blood

pressure)

2. Carotid sinus transmits via glossopharyngeal nerve to medulla

Baroreceptors:

1. Hypotension: . arterial pressure ..stretch ..afferent baroreceptor firing .

. efferent sympathetic firing and . efferent parasympathetic stimulation .

vasoconstriction, . HR, . contractility, . BP. Important in the response to severe

hemorrhage.

2. Carotid massage: . pressure on carotid artery ..stretch .. HR.

Chemoreceptors:

1. Peripheral: Carotid and aortic bodies respond to . PO2 (< 60 mmHg), . PCO2,

and . pH of blood.

2. Central: Respond to changes in pH and PCO2 of brain interstitial fluid, which in

turn are influenced by arterial CO2. Do not directly respond to PO2. Responsible

for Cushing reaction, response to cerebral ischemia, response to . intracranial

pressure .hypertension (sympathetic response) and bradycardia (parasympathetic

response).

Circulation through organs

Liver Largest share of systemic cardiac output.

Kidney Highest blood flow per gram of tissue.

Heart Large arteriovenous O2 difference. . O2 demand is met by . coronary blood flow, not by

. extraction of O2.

CARDIOVASCULAR HIGH-YI E LD SYSTEMS

. RENIN-ANGIOTENSIN SYSTEM

(kidneys)

MAP

ß1 (. heart rate, . contractility)- . CO

a1 (venoconstriction: . venous return)-. CO

a1 (arteriolar vasoconstriction)- . TPR

Medullary vasomotor

center senses .

baroreceptor firing

MAP

. SYMPATHETIC ACTIVITY

(heart and vasculature)

JGA senses . ECV

(effective circulating volume)

Angiotensin II (vasoconstriction)- . TPR

Aldosterone (. blood volume)-. CO

Aortic

chemoreceptor

Carotid

body

(chemoreceptor)

Aortic

baroreceptor

Carotid

baroreceptor

Carotid

sinus

Normal pressures

PCWP–pulmonary capillary

wedge pressure (in mmHg)

is a good approximation of

left atrial pressure.

Measured with Swan-Ganz

catheter.

Autoregulation Mechanism–blood flow is altered to meet demands of tissue.

Organ Factors determining autoregulation Note: the pulmonary

Heart Local metabolites: O2, adenosine, NO vasculature is unique in that

Brain Local metabolites: CO2 (pH) hypoxia causes

Kidneys Myogenic and tubuloglomerular feedback vasoconstriction (in other

Lungs Hypoxia causes vasoconstriction organs hypoxia causes

Skeletal muscle Local metabolites: lactate, adenosine, K+ vasodilation).

Skin Sympathetic stimulation most important

mechanism–temperature control

Capillary fluid Starling forces determine fluid movement by osmosis through capillary membranes:

exchange 1. Pc = capillary pressure–moves fluid out of capillary

2. Pi = interstitial fluid pressure–moves fluid into capillary

3. pc = plasma colloid osmotic pressure–moves fluid into capillary

4. pi = interstitial fluid colloid osmotic pressure–moves fluid out

of capillary

Thus, net filtration pressure = Pnet = [(Pc – Pi) – (pc – pi)].

Kf = filtration constant (capillary permeability).

Net fluid flow = (Pnet) (Kf).

Edema–excess fluid outflow into interstitium commonly caused by:

1. . capillary pressure (. Pc; heart failure)

2. . plasma proteins (. pc; nephrotic syndrome, liver failure)

3. . capillary permeability (. Kf; toxins, infections, burns)

4. . interstitial fluid colloid osmotic pressure (. pi; lymphatic blockage)

227

HIGH-YI E LD SYSTEMS CARDIOVASCULAR

<25/<5

<25/10

<5

<130/10

<12 PCWP

<130/90

<12

pi Pi

Pc pc

228

CARDIOVASCULAR-PATHOLOGY

Common congenital 1. Heart defects

malformations 2. Hypospadias

3. Cleft lip (with or without cleft palate)

4. Congenital hip dislocation

5. Spina bifida

6. Anencephaly

7. Pyloric stenosis Associated with projectile

vomiting.

Congenital heart disease

Right-to-left shunts 1. Tetralogy of Fallot (most common cause of early The 3 T’s:

(early cyanosis)– cyanosis) Tetralogy

“blue babies” 2. Transposition of great vessels Transposition

3. Truncus arteriosus Truncus

Children may squat to

. venous return.

Left-to-right shunts 1. VSD (most common congenital cardiac anomaly) Frequency–VSD > ASD > PDA.

(late cyanosis)– 2. ASD (loud S1; wide, fixed split S2) . pulmonary resistance due

“blue kids” 3. PDA (close with indomethacin) to arteriolar thickening.

. progressive pulmonary

hypertension; R . L shunt

(Eisenmenger’s).

Eisenmenger’s Uncorrected VSD, ASD, or PDA leads to progressive

syndrome pulmonary hypertension. As pulmonary resistance

., the shunt reverses from L . R to R . L, which

causes late cyanosis (clubbing and polycythemia).

Tetralogy of Fallot 1. Pulmonary stenosis (most important determinant PROVe.

for prognosis)

2. RVH

3. Overriding aorta (overrides the VSD)

4. VSD

Early cyanosis is caused by a right-to-left shunt

across the VSD. On x-ray, boot-shaped heart

due to RVH. Patients suffer “cyanotic spells.”

Tetralogy of Fallot is caused by anterosuperior

displacement of the infundibular septum.

CARDIOVASCULAR HIGH-YI E LD SYSTEMS

RVH

VSD

R

L

4

2

3

1

(Adapted, with permission, from Chandrasoma P. Concise Pathology, 3rd ed. Stamford, CT: Appleton & Lange, 1997:345. )

229

Transposition of Aorta leaves RV (anterior) and pulmonary trunk Due to failure of the

great vessels leaves LV (posterior) .separation of systemic and aorticopulmonary septum

pulmonary circulations. Not compatible with life to spiral.

unless a shunt is present to allow adequate mixing Without surgical correction,

of blood (e.g., VSD, PDA, or patent foramen most infants die within the

ovale). first few months of life.

Coarctation of aorta

Infantile type–aortic stenosis proximal to insertion Male-to-female ratio 3:1.

of ductus arteriosus (preductal). Check femoral pulses on

Adult type–stenosis is distal to ductus arteriosus physical exam.

(postductal). Associated with notching of the ribs, INfantile: IN close to

hypertension in upper extremities, weak pulses in the heart.

lower extremities. ADult: Distal to Ductus.

Patent ductus In fetal period, shunt is right to left (normal). In Indomethacin is used to close a

arteriosus neonatal period, lung resistance . and shunt PDA. PGE is used to keep a

becomes left to right with subsequent RVH PDA open, which may be

and failure (abnormal). Associated with a necessary to sustain life in

continuous, “machine-like” murmur. Patency is conditions such as

maintained by PGE synthesis and low O2 tension. transposition of the great

vessels.

Congenital cardiac Disorder Defect

defect associations 22q11 syndromes Truncus arteriosus, tetralogy

of Fallot

Down syndrome ASD, VSD

Congenital rubella Septal defects, PDA

Turner’s syndrome Coarctation of aorta

Marfan’s syndrome Aortic insufficiency

Offspring of diabetic mother Transposition of great vessels

HIGH-YI E LD SYSTEMS CARDIOVASCULAR

(Adapted, with permission, from Way LW (ed). Current Surgical Diagnosis

and Treatment, 10th ed. Stamford, CT: Appleton & Lange,

1994:405.)

Aorta

Left ventricle

Ventricular septum

Pulmonary artery

Right

ventricle

Descending aorta

Ligamentum arteriosum

Postductal

coarctation

Aorta

Ductus

arteriosus

(patent)

Pulmonary

artery

230

CARDIOVASCULAR-PATHOLOGY (continued)

Hypertension Defined as BP = 140/90.

Risk factors . age, obesity, diabetes, smoking, genetics, black > white > Asian.

Features 90% of hypertension is 1° (essential) and related to . CO or . TPR; remaining 10%

mostly 2° to renal disease. Malignant hypertension is severe and rapidly progressing.

Predisposes to Atherosclerosis, stroke, CHF, renal failure, retinopathy, and aortic dissection.

Hyperlipidemia signs

Atheromata Plaques in blood vessel walls.

Xanthoma Plaques or nodules composed of lipid-laden histiocytes in the skin, especially the

eyelids.

Tendinous xanthoma Lipid deposit in tendon, especially Achilles.

Corneal arcus Lipid deposit in cornea, nonspecific (arcus senilis).

Arteriosclerosis

Mönckeberg Calcification of the arteries, especially radial or ulnar. Usually benign.

Arteriolosclerosis Hyaline thickening of small arteries in essential hypertension. Hyperplastic “onion

skinning” in malignant hypertension.

Atherosclerosis Fibrous plaques and atheromas form in intima of arteries.

Atherosclerosis Disease of elastic arteries and large and medium-sized muscular arteries (see Color

Image 79).

Risk factors Smoking, hypertension, diabetes mellitus, hyperlipidemia, family history.

Progression Fatty streaks . proliferative plaque . complex atheromas.

Complications Aneurysms, ischemia, infarcts, peripheral vascular disease, thrombus, emboli.

Location Abdominal aorta > coronary artery > popliteal artery > carotid artery.

Symptoms Angina, claudication, but can be asymptomatic.

Ischemic heart Possible manifestations:

disease 1. Angina (CAD narrowing > 75%):

a. Stable–mostly 2° to atherosclerosis (retrosternal chest pain with exertion)

b. Prinzmetal’s variant–occurs at rest 2° to coronary artery spasm

c. Unstable/crescendo–thrombosis but no necrosis (worsening chest pain)

2. Myocardial infarction–most often acute thrombosis due to coronary artery

atherosclerosis. Results in myocyte necrosis.

3. Sudden cardiac death–death from cardiac causes within 1 hour of onset of

symptoms, most commonly due to a lethal arrhythmia

4. Chronic ischemic heart disease–progressive onset of CHF over many years

due to chronic ischemic myocardial damage

CARDIOVASCULAR HIGH-YI E LD SYSTEMS

231

Infarcts: Red (hemorrhagic) infarcts occur in loose tissues REd = REperfusion.

red vs. pale with collaterals, such as lungs, intestine, or

following reperfusion.

Pale infarcts occur in solid tissues with single blood

supply, such as brain, heart, kidney, and spleen.

HIGH-YI E LD SYSTEMS CARDIOVASCULAR Pale

infarcts

Heart Kidney

Red

infarcts

Liver Lung

232

CARDIOVASCULAR-PATHOLOGY (continued)

Evolution of MI Coronary artery occlusion: LAD > RCA > circumflex.

Symptoms: Diaphoresis, nausea, vomiting, severe retrosternal pain, pain in left arm

and/or jaw, shortness of breath, fatigue, adrenergic symptoms (see Color Image 80).

CARDIOVASCULAR HIGH-YI E LD SYSTEMS

Hyperemia

Recanalized

artery

Gray-white

Occluded

artery

No visible change by light

microscopy in first 2-4

hours.

Infarct

Dark mottling;

pale with

tetrazolium

stain

Hyperemic border;

central yellow-brown

softening–

maximally yellow

and soft by 10 days

A. First day

B. 2 to 4 days

C. 5 to 10 days

D. 7 weeks

Coagulative necrosis; contraction

bands visible after 4 hours.

Release of contents of necrotic

cells into bloodstream and the

beginning of neutrophil

emigration

Tissue surrounding infarct

shows acute inflammation

Dilated vessels (hyperemia)

Neutrophil emigration

Muscle shows extensive

coagulative necrosis

Outer zone (ingrowth of

granulation tissue)

Macrophages

Neutrophils

Contracted scar complete

(Adapted, with permission, from Chandrasoma P. Pathology Notes. Stamford, CT: Appleton & Lange, 1991:244.)

233

Diagnosis of MI In the first 6 hours, ECG is the gold standard.

Cardiac troponin I rises after 4 hours and is elevated

for 7-10 days; more specific than other protein

markers.

CK-MB is predominantly found in myocardium but

can also be released from skeletal muscle.

AST is nonspecific and can be found in cardiac, liver,

and skeletal muscle cells.

ECG changes can include ST elevation (transmural

infarct), ST depression (subendocardial infarct),

and pathological Q waves (transmural infarct).

MI complications 1. Cardiac arrhythmia–important cause of death before reaching hospital; common in

first few days

2. LV failure and pulmonary edema

3. Cardiogenic shock (large infarct–high risk of mortality)

4. Rupture of ventricular free wall, interventricular septum, papillary muscle (4-10 days

post-MI), cardiac tamponade

5. Aneurysm formation–. CO, risk of arrhythmia, embolus from mural thrombus

6. Fibrinous pericarditis–friction rub (3-5 days post-MI)

7. Dressler’s syndrome–autoimmune phenomenon resulting in fibrinous pericarditis

(several weeks post-MI)

Cardiomyopathies

Dilated (congestive) Most common cardiomyopathy (90% of cases). Systolic dysfunction ensues.

cardiomyopathy Etiologies include chronic Alcohol abuse,

Beriberi, Coxsackie B virus myocarditis, chronic

Cocaine use, Chagas’ disease, Doxorubicin

toxicity, peripartum cardiomyopathy, and

hemochromatosis. Heart dilates and looks like a

balloon on chest x-ray.

Hypertrophic Hypertrophy often asymmetric and involving the Diastolic dysfunction ensues.

cardiomyopathy intraventricular septum. 50% of cases are familial,

autosomal dominant. Cause of sudden death in

young athletes. Findings: loud S4, apical

impulses, systolic murmur. Treat with ß-blocker.

Restrictive/obliterative Major causes include sarcoidosis, amyloidosis,

cardiomyopathy postradiation fibrosis, endocardial fibroelastosis,

and endomyocardial fibrosis (Löffler’s).

HIGH-YI E LD SYSTEMS CARDIOVASCULAR

Troponin

CK-MB

AST LDH1

Days

1 2

Pain

234

CARDIOVASCULAR-PATHOLOGY (continued)

Heart murmurs

S1 S2

Mitral regurgitation Holosystolic high-pitched “blowing murmur.” Loudest at apex.

Aortic stenosis Crescendo-decrescendo systolic ejection murmur following

ejection click. LV >> aortic pressure during systole. Radiates to

carotids/apex. “Pulsus parvus et tardus” pulses weak compared

to heart sounds.

VSD Holosystolic murmur.

Mitral prolapse Late systolic murmur with midsystolic click. Most frequent

valvular lesion.

Aortic regurgitation Immediate high-pitched “blowing” diastolic murmur. Wide pulse

pressure.

Mitral stenosis Follows opening snap. Delayed rumbling late diastolic murmur. LA

>> LV pressure during diastole. Tricuspid stenosis differs because

it gets louder with inspiration.

PDA Continuous machine-like murmur. Loudest at time of S2.

Cardiac tumors Myxomas are the most common 1° cardiac tumor in adults. 90% occur in the atria

(mostly LA). Myxomas are usually described as a “ball-valve” obstruction in the LA.

Rhabdomyomas are the most frequent 1° cardiac tumor in children (associated with

tuberous sclerosis).

Metastases most common heart tumor (see Color Image 88).

CARDIOVASCULAR HIGH-YI E LD SYSTEMS

(Adapted, with permission, from Wood P. Diseases of the Heart and Circulation, 3rd ed. Baltimore: Lippincott, 1968.)

235

CHF

Abnormality Cause

Dyspnea on exertion Failure of LV output to .

during exercise.

Cardiac dilation Greater ventricular end-diastolic

volume.

Pulmonary edema, LV failure . . pulmonary

paroxysmal venous pressure .

nocturnal dyspnea pulmonary venous

distention and transudation

of fluid. Presence of

hemosiderin-laden

macrophages (“heart failure”

cells).

Orthopnea (shortness . venous return in supine

of breath when position exacerbates pulmonary

supine) vascular congestion.

Hepatomegaly . central venous pressure

(nutmeg liver) . . resistance to portal flow.

Rarely, leads to “cardiac

cirrhosis.”

Ankle, sacral edema RV failure . . venous pressure

. fluid transudation.

Embolus types Fat, Air, Thrombus, Bacteria, Amniotic fluid, An embolus moves like a FAT

Tumor. Fat emboli are associated with long BAT. Approximately 95% of

bone fractures and liposuction. Amniotic fluid pulmonary emboli arise from

emboli can lead to DIC, especially postpartum. deep leg veins.

Pulmonary embolus–chest pain, tachypnea,

dyspnea.

Deep venous Predisposed by Virchow’s triad:

thrombosis 1. Stasis

2. Hypercoagulability

3. Endothelial damage

Cardiac Compression of heart by fluid (i.e., blood) in pericardium, leading to . CO.

tamponade Equilibration of pressures in all 4 chambers.

Findings: hypotension, . venous pressure (JVD), distant heart sounds.

Pulsus paradoxus; ECG shows electrical alternans (beat-to-beat alterations of QRS

complex height).

HIGH-YI E LD SYSTEMS CARDIOVASCULAR

. LV contractility

Pulmonary

edema

Peripheral

edema

Pulmonary venous

congestion

. cardiac

output

. RV output

. systemic venous

pressure

. preload, . cardiac

output (compensation)

. renal Na+

and H2O

reabsorption

. LV

contractility

. sympathetic

activity

. reninangiotensinaldosterone

236

CARDIOVASCULAR-PATHOLOGY (continued)

Bacterial New murmur, anemia, fever, Osler’s nodes (tender Mitral valve is most frequently

endocarditis raised lesions on finger or toe pads), Roth’s spots involved. Tricuspid valve

(round white spots on retina surrounded by endocarditis is associated

hemorrhage), Janeway lesions (small erythematous with IV drug abuse.

lesions on palm or sole), splinter hemorrhages Complications:

on nail bed. Valvular damage may cause new chordae rupture,

murmur. Multiple blood cultures necessary for glomerulonephritis,

diagnosis (see Color Image 82). suppurative pericarditis,

1. Acute–S. aureus (high virulence). Large emboli.

vegetations on previously normal valves. Bacteria FROM JANE:

Rapid onset. Fever

2. Subacute–viridans streptococcus (low Roth’s spots

virulence). Smaller vegetations on Osler’s nodes

congenitally abnormal or diseased valves. Murmur

Sequela of dental procedures. More Janeway lesions

insidious onset. Anemia

Endocarditis may also be nonbacterial 2° to Nail-bed hemorrhage

metastasis or renal failure (marantic/thrombotic Emboli

endocarditis).

Libman-Sacks Vegetations develop on both sides of valve (. mitral SLE causes LSE.

endocarditis valve stenosis) but do not embolize. Seen in

lupus.

Rheumatic heart Rheumatic fever is a consequence of pharyngeal FEVERSS:

disease infection with group A ß-hemolytic Fever

streptococci. Late sequelae include rheumatic Erythema marginatum

heart disease, which affects heart valves– Valvular damage

mitral > aortic >> tricuspid (high-pressure valves ESR .

affected most). Associated with Aschoff bodies, Red-hot joints (polyarthritis)

migratory polyarthritis, erythema marginatum, Subcutaneous nodules

elevated ASO titers. St. Vitus’ dance (chorea)

Immune mediated, not direct effect of bacteria

(see Color Image 85).

Aschoff body Aschoff bodies (granuloma with giant cells) and Think of two RHussians with

Anitschkow’s cells (activated histiocytes) are RHeumatic heart disease

found in rheumatic heart disease. (Aschoff and Anitschkow).

Pericarditis

Serous Caused by SLE, rheumatoid arthritis, infection, uremia.

Fibrinous Uremia, MI, rheumatic fever.

Hemorrhagic TB, malignancy (e.g., melanoma).

Findings: pericardial pain, friction rub, ECG changes (diffuse ST elevations in all leads),

pulsus paradoxus, distant heart sounds.

Can resolve without scarring or lead to chronic adhesive or chronic constrictive

pericarditis.

CARDIOVASCULAR HIGH-YI E LD SYSTEMS

237

Syphilitic heart 3° syphilis disrupts the vasa vasora of the aorta Can result in aneurysm of the

disease with consequent dilation of the aorta and valve ring. ascending aorta or aortic

Often affects the aortic root and calcification of arch and aortic valve

ascending arch of the aorta. incompetence.

May see calcification of the aortic root and ascending

aortic arch.

HIGH-YI E LD SYSTEMS CARDIOVASCULAR

238 CARDIOVASCULAR HIGH-YI E LD SYSTEMS

CARDIOVASCULAR-PHARMACOLOGY

Cardiovascular therapy

(Adapted, with permission, from Katzung BG, Trevor AJ. USMLE Road Map: Pharmacology, 1st ed. New York: McGraw-Hill, 2003:39.)

Cardiac output

Carotid sinus

firing

Sympathetic

discharge

Renin

release

Vasodilators

– –

Angiotensin II

Renal blood

flow

Force

Rate

Preload

Afterload

Remodeling

Positive inotropic

drugs +

ß-Blockers

ACE inhibitors

Diuretics

AII antagonists –

239

HIGH-YI E LD SYSTEMS CARDIOVASCULAR

Antihypertensive drugs

Drug Adverse effects

Diuretics

Hydrochlorothiazide Hypokalemia, slight hyperlipidemia, hyperuricemia, lassitude, hypercalcemia, hyperglycemia

Loop diuretics Potassium wasting, metabolic alkalosis, hypotension, ototoxicity

Sympathoplegics

Clonidine Dry mouth, sedation, severe rebound hypertension

Methyldopa Sedation, positive Coombs’ test

Hexamethonium Severe orthostatic hypotension, blurred vision, constipation, sexual dysfunction

Reserpine Sedation, depression, nasal stuffiness, diarrhea

Guanethidine Orthostatic and exercise hypotension, sexual dysfunction, diarrhea

Prazosin 1st-dose orthostatic hypotension, dizziness, headache

ß-blockers Impotence, asthma, cardiovascular effects (bradycardia, CHF, AV block), CNS effects

(sedation, sleep alterations)

Vasodilators

Hydralazinea Nausea, headache, lupus-like syndrome, reflex tachycardia, angina, salt retention

Minoxidila Hypertrichosis, pericardial effusion, reflex tachycardia, angina, salt retention

Nifedipine, Dizziness, flushing, constipation (verapamil), nausea

verapamil

Nitroprusside Cyanide toxicity (releases CN)

ACE inhibitors

Captopril Hyperkalemia, Cough, Angioedema, Proteinuria, Taste changes, hypOtension,

Pregnancy problems (fetal renal damage), Rash, Increased renin, Lower

angiotensin II

Angiotensin II

receptor

inhibitors

Losartan Fetal renal toxicity, hyperkalemia

aUse with ß-blockers to prevent reflex tachycardia, diuretic to block salt retention.

Hydralazine

Mechanism . cGMP .smooth muscle relaxation. Vasodilates arterioles > veins; afterload reduction.

Clinical use Severe hypertension, CHF.

Toxicity Compensatory tachycardia, fluid retention. Lupus-like syndrome.

Calcium channel Nifedipine, verapamil, diltiazem.

blockers

Mechanism Block voltage-dependent L-type calcium channels of cardiac and smooth muscle and

thereby reduce muscle contractility.

Vascular smooth muscle–nifedipine > diltiazem > verapamil.

Heart–verapamil > diltiazem > nifedipine.

Clinical use Hypertension, angina, arrhythmias (not nifedipine).

Toxicity Cardiac depression, peripheral edema, flushing, dizziness, and constipation.

240 CARDIOVASCULAR HIGH-YI E LD SYSTEMS

CARDIOVASCULAR-PHARMACOLOGY (continued)

Nitroglycerin, isosorbide dinitrate

Mechanism Vasodilate by releasing nitric oxide in smooth muscle, causing . in cGMP and smooth

muscle relaxation. Dilate veins >> arteries. . preload.

Clinical use Angina, pulmonary edema. Also used as an aphrodisiac and erection enhancer.

Toxicity Tachycardia, hypotension, headache, “Monday disease” in industrial exposure,

development of tolerance for the vasodilating action during the work week and loss of

tolerance over the weekend, resulting in tachycardia, dizziness, and headache.

Antianginal Goal–reduction of myocardial O2 consumption (MVO2) by decreasing 1 or more of the

therapy determinants of MVO2: end diastolic volume, blood pressure, heart rate, contractility,

ejection time.

Nitrates ß-blockers Nitrates +

Component (affect preload) (affect afterload) ß-blockers

End diastolic volume. . No effect or .

Blood pressure . . .

Contractility . (reflex . Little/no effect

response)

Heart rate . (reflex . .

response)

Ejection time . . Little/no effect

MVO2 . . ..

Calcium channel blockers–Nifedipine is similar to Nitrates in effect; verapamil is

similar to ß-blockers in effect.

241

HIGH-YI E LD SYSTEMS CARDIOVASCULAR

Cardiac drugs: sites of action

Cardiac glycosides Digoxin–75% bioavailability, 20-40% protein bound, t1/2 = 40 hours, urinary excretion.

Mechanism Inhibit the Na+/K+ ATPase of cell membrane, causing . intracellular Na+. Na+-Ca2+

antiport does not function as efficiently, causing . intracellular Ca2+; leads to positive

inotropy. May cause . PR, . QT, scooping of ST segment, T-wave inversion on ECG.

Clinical use CHF (. contractility); atrial fibrillation (. conduction at AV node).

Toxicity Nausea, vomiting, diarrhea. Blurry yellow vision (think Van Gogh). Arrhythmia.

Toxicities of digoxin are . by renal failure (. excretion), hypokalemia (potentiates

drug’s effects), and quinidine (. digoxin clearance; displaces digoxin from tissue

binding sites).

Antidote Slowly normalize K+, lidocaine, cardiac pacer, anti-dig Fab fragments.

Cardiac sarcomere is shown above with the cellular components involved in excitationcontraction

coupling. Factors involved in excitation-contraction coupling are

numbered. (1) Na+/K+ ATPase; (2) Na+-Ca2+ exchanger; (3) voltage-gated calcium

channel; (4) calcium pump in the wall of the sarcoplasmic reticulum (SR);

(5) calcium release channel in the SR; (6) site of calcium interaction with

troponin-tropomyosin system.

(Adapted, with permission, from Katzung BG. Basic and Clinical Pharmacology, 7th ed. Stamford, CT: Appleton

& Lange, 1998:198.)

+

Digitalis

K+ Na+ Ca2+

1 2

4

4

Cell membrane 1 2

Extracellular

space

Ca2+ channel

blockers

ß-blockers

“Trigger” calcium

Cytoplasm

Ryanodine

“Ca2+ sensitizers”

Actin Myosin

Ca2+

3

5

Ca2+

6

4

SR

4

ZZ

Z

ZZ

Z

+

3

5

+

242 CARDIOVASCULAR HIGH-YI E LD SYSTEMS

CARDIOVASCULAR-PHARMACOLOGY (continued)

Antiarrhythmics- Local anesthetics. Slow or block (.) conduction (especially in depolarized cells).

Na+ channel . slope of phase 4 depolarization and . threshold for firing in abnormal pacemaker

blockers (class I) cells. Are state dependent (selectively depress tissue that is frequently depolarized,

e.g., fast tachycardia).

Class IA Quinidine, Amiodarone, Procainamide, Disopyramide. “Queen Amy Proclaims

. AP duration, . effective refractory period (ERP), Diso’s pyramid.”

. QT interval. Affect both atrial and ventricular

arrhythmias.

Toxicity: quinidine (cinchonism–headache, tinnitus;

thrombocytopenia; torsades de pointes due to .

QT interval); procainamide (reversible SLE-like

syndrome).

Class IB Lidocaine, mexiletine, tocainide. . AP duration.

Affect ischemic or depolarized Purkinje and

ventricular tissue. Useful in acute ventricular

arrhythmias (especially post-MI) and in

digitalis-induced arrhythmias.

Toxicity: local anesthetic. CNS stimulation/depression,

cardiovascular depression.

Class IC Flecainide, encainide, propafenone. No effect on

AP duration. Useful in V-tachs that progress to VF

and in intractable SVT. Usually used only as last

resort in refractory tachyarrhythmias.

Toxicity: proarrhythmic, especially post-MI

(contraindicated).

Class IA

Class IB

Class IC

Phase 3 (IK)

All class I drugs

0 mV

Phase 0

INa

-85 mV

Outside

Membrane

Inside

All class I drugs Action potential currents

Na+

Na+

Ca2+

Ca2+

K+ K+

All class I drugs

Diastolic currents

ERP

(Adapted, with permission, from Katzung BG, Trevor AJ. Pharmacology: Examination & Board Review, 5th ed.

Stamford, CT: Appleton & Lange, 1998:118.)

243

Antiarrhythmics- Propranolol, esmolol, metoprolol, atenolol, timolol.

ß-blockers

(class II)

Mechanism . cAMP, . Ca2+ currents. Suppress abnormal pacemakers by . slope of phase 4.

AV node particularly sensitive–. PR interval. Esmolol very short acting.

Toxicity Impotence, exacerbation of asthma, cardiovascular effects (bradycardia, AV block,

CHF), CNS effects (sedation, sleep alterations). May mask the signs of hypoglycemia.

Antiarrhythmics- Sotalol, ibutilide, bretylium, amiodarone.

K+ channel

blockers (class III)

Mechanism . AP duration, . ERP. Used when other

antiarrhythmics fail. . QT interval.

Toxicity Sotalol–torsades de pointes, excessive ß block; Remember to check PFTs,

ibutilide–torsades; bretylium–new arrhythmias, LFTs, and TFTs when

hypotension; amiodarone–pulmonary fibrosis, using amiodarone.

corneal deposits, hepatotoxicity, skin deposits

resulting in photodermatitis, neurologic effects,

constipation, cardiovascular effects (bradycardia,

heart block, CHF), hypothyroidism/

hyperthyroidism.

HIGH-YI E LD SYSTEMS CARDIOVASCULAR

0 mV

-85 mV

Outside

Membrane

Inside

ERP

K+

Phase 3 (IK)

Action potential currents

Na+

Na+

Ca2+

K+ Ca2+

Class III action

Diastolic currents

Class III action

(Adapted, with permission, from Katzung BG, Trevor AJ. Pharmacology:

Examination & Board Review, 5th ed. Stamford, CT: Appleton & Lange,

1998:120.)

244

CARDIOVASCULAR-PHARMACOLOGY (continued)

Antiarrhythmics- Verapamil, diltiazem.

Ca2+ channel

blockers (class IV)

Mechanism Primarily affect AV nodal cells. . conduction velocity, . ERP, . PR interval. Used in

prevention of nodal arrhythmias (e.g., SVT).

Toxicity Constipation, flushing, edema, CV effects (CHF, AV block, sinus node depression);

torsades de pointes (bepridil).

Other antiarrhythmics

Adenosine Drug of choice in diagnosing/abolishing AV nodal arrhythmias.

K+ Depresses ectopic pacemakers, especially in digoxin toxicity.

Mg+ Effective in torsades de pointes and digoxin toxicity.

CARDIOVASCULAR HIGH-YI E LD SYSTEMS

(Adapted, with permission, from Katzung BG, Trevor AJ. Pharmacology: Examination & Board Review, 5th ed.

Stamford, CT: Appleton & Lange, 1998:121.)

Phase 2 (ICa and IK)

Note .

0 mV

Phase 0

ICa

-75 mV

Outside

Membrane

Inside

Action potential currents

Na+

Ca2+

K+

Class IV action

Class IV action

ERP

K+ Na+ Ca2+

Diastolic currents

High-Yield Clinical

Vignettes

Anatomy

Physiology

Pathology

Pharmacology

H I G H -Y I E L D S Y S T E M S

Endocrine

245

“Chocolate causes certain endocrine glands to secrete hormones that affect

your feelings and behavior by making you happy.”

–Elaine Sherman, Book of Divine Indulgences

246

ENDOCRINE-HIGH-YIELD C LI N ICAL VIGNETTES

Woman presents with diffuse What are the expected Low TSH and high thyroid

goiter and hyperthyroidism. values of TSH and hormones.

thyroid hormones?

48-year-old female presents with What is the diagnosis? Hypothyroidism.

progressive lethargy and extreme

sensitivity to cold temperatures.

Patient with elevated serum What is the diagnosis? Pituitary tumor.

cortisol levels undergoes a

dexamethasone suppression

test. 1 mg of dexamethasone

does not . cortisol levels, but

8 mg does.

50-year-old man complains of What is the diagnosis? Carcinoid syndrome.

diarrhea. On physical exam,

his face is plethoric and a heart

murmur is detected.

Woman of short stature presents What endocrine Albright’s hereditary

with shortened 4th and 5th disorder comes to mind? osteodystrophy, or

metacarpals. pseudohypoparathyroidism.

Nondiabetic patient presents What is the diagnosis? Surreptitious insulin injection.

with hypoglycemia but low

levels of C peptide.

ENDOCRINE HIGH-YI E LD SYSTEMS

247

ENDOCRINE-ANATOMY

Adrenal cortex and medulla

GFR corresponds with Salt

(Na+), Sugar

(glucocorticoids), and Sex

(androgens).

“The deeper you go, the

sweeter it gets.”

Pheochromocytoma–most

common tumor of the adrenal

medulla in adults.

Neuroblastoma–most

common in children.

Pheochromocytoma causes

episodic hypertension;

neuroblastoma does not.

Adrenal gland Left adrenal . left adrenal vein . left renal vein . IVC.

drainage Right adrenal . right adrenal vein . IVC.

Pituitary gland Posterior pituitary . vasopressin and oxytocin, made Acidophils–GH, prolactin.

in the hypothalamus and shipped to pituitary.

Derived from neuroectoderm.

Anterior pituitary . FSH, LH, ACTH, GH, TSH, FLAT PiG:

melanotropin (MSH), prolactin. Derived from FSH

oral ectoderm. LH

a subunit–common subunit to TSH, LH, FSH, and ACTH

hCG. TSH

ß subunit–determines hormone specificity. Prolactin

GH

Endocrine pancreas Islets of Langerhans are collections of a, ß, and d endocrine cells (most numerous

cell types in tail of pancreas). Islets arise from pancreatic buds. a = glucagon; ß = insulin;

d = somatostatin.

HIGH-YI E LD SYSTEMS ENDOCRINE

Primary

regulatory control Anatomy Secretory products

Capsule

Renin-angiotensin . Zona . Aldosterone

Glomerulosa

ACTH, hypothalamic . Zona . Cortisol,

CRH Fasciculata sex hormones

ACTH, hypothalamic . Zona . Sex hormones

CRH Reticularis (e.g., androgens)

Preganglionic . Medulla . Catecholamines

sympathetic fibers (Epi, NE)

Cortex (from mesoderm)

Medulla (from neural crest)

Chromaffin cells

248

ENDOCRINE-PHYSIOLOGY

Prolactin Prolactin . dopamine synthesis and secretion from the hypothalamus. Dopamine

regulation subsequently inhibits prolactin secretion. Dopamine agonists (e.g., bromocriptine)

therefore inhibit prolactin secretion, whereas dopamine antagonists (e.g., most

antipsychotics) stimulate prolactin secretion. In females, prolactin inhibits GnRH

synthesis and release, which inhibits ovulation. Amenorrhea is commonly seen in

prolactinomas.

ENDOCRINE HIGH-YI E LD SYSTEMS

Prolactin regulation

+

+

+

Dopamine TRH

Anterior pituitary

Hypothalamus

Prolactin

Adrenal steroids

249

HIGH-YI E LD SYSTEMS ENDOCRINE

A = 17-hydroxylase deficiency. . sex hormones, . cortisol, . mineralocorticoids. Cx = HYPERtension,

hypokalemia; phenotypically female but no maturation.

B = 21ß-hydroxylase deficiency. Most common form. . cortisol (increased ACTH), . mineralocorticoids,

. sex hormones. Cx = masculinization, female pseudohermaphroditism, HYPOtension, hyponatremia,

hyperkalemia, . plasma renin activity, and volume depletion. Salt wasting can lead to hypovolemic

shock in the newborn.

C = 11ß-hydroxylase deficiency. . cortisol, . aldosterone and corticosterone, . sex hormones.

Cx = masculinization, HYPERtension (11-deoxycorticosterone acts as a weak mineralocorticoid).

Congenital

adrenal

hyperplasias

Cholesterol

Desmolase

ACTH Ketoconazole

Pregnenolone

17a-hydroxyprogesterone

Dehydroepiandrosterone (DHEA)

Progesterone

17-hydroxypregnenolone

Androstenedione

11-deoxycorticosterone Testosterone

5a-reductase

DHT

Estrone

11-deoxycortisol Estradiol

Corticosterone Cortisol

Aldosterone

Mineralocorticoids

C21

Glucocorticoids

21C

Androgens

C19

Estrogens

C18

A

Aldosterone

synthase

+

Angiotensin II

+

A

B

C

B

C

Aromatase

250

ENDOCRINE-PHYSIOLOGY (continued)

PTH

Source Chief cells of parathyroid.

Function 1. . bone resorption of calcium and phosphate PTH . serum Ca2+, . serum

2. . kidney reabsorption of calcium in distal (PO4)3-, . urine (PO4)3-.

convoluted tubule PTH stimulates both

3. . kidney reabsorption of phosphate osteoclasts and osteoblasts.

4. . 1,25-(OH)2 vitamin D (cholecalciferol) PTH = Phosphate Trashing

production by stimulating kidney Hormone.

1a-hydroxylase

Regulation . in free serum Ca2+ . PTH secretion.

Shown above are the main actions of PTH and 1,25-(OH)2D in the maintenance of

calcium (A) and phosphate (B) homeostasis.

ENDOCRINE HIGH-YI E LD SYSTEMS

Four

parathyroid

glands

+

Low ionized calcium

Feedback

inhibition

of PTH

secretion

  • Stimulates reabsorption

of calcium

  • Inhibits phosphate

reabsorption

  • Stimulates production of

1,25-(OH)2D

Bone

  • Stimulates calcium release

from bone mineral compartment

  • Directly stimulates osteoblastic

cells, indirectly stimulates

osteoclastic cells

  • Stimulates bone resorption via

indirect effect on osteoclasts

  • Enhances bone matrix

degradation

  • Increases intestinal

calcium reabsorption

  • Releases phosphate

from matrix

  • Increases calcium and phosphate

reabsorption

Renal

tubular cells

Increases serum calcium

Lower serum

phosphorus

. conversion

25-(OH)D . 1,25-(OH)2D

  • . urinary cAMP

PTH (1-84)

released into

circulation

A.

B.

(Adapted, with permission, from Chandrasoma P et al. Concise Pathology, 3rd ed.

Stamford, CT: Appleton & Lange, 1998.)

251

Vitamin D

Source Vitamin D3 from sun exposure in skin. D2 from If you do not get vitamin D,

plants. Both converted to 25-OH vitamin D in you get rickets (kids) or

liver and to 1,25-(OH)2 vitamin D (active form) osteomalacia (adults).

in kidney. 24,25-(OH)2 vitamin D is an

Function 1. . absorption of dietary calcium inactive form of vitamin D.

2. . absorption of dietary phosphate

3. . bone resorption of Ca2+ and (PO4)3-

Regulation . PTH causes . 1,25-(OH)2 vitamin D formation.

. [Ca2+] . 1,25-(OH)2 vitamin D production.

. phosphate causes . 1,25-(OH)2 vitamin D

conversion.

1,25-(OH)2 vitamin D feedback inhibits its own

production.

Calcium, phosphate, and alkaline phosphatase levels

Ca2+ Phosphate Alkaline phosphatase

Hyperparathyroidism . . .

Paget’s disease of bone N/. N …

Vitamin D intoxication . . N/.

Osteoporosis N N N

Renal insufficiency . . N

N = no change.

Calcitonin

Source Parafollicular cells (C cells) of thyroid. Calcitonin opposes actions of

Function . bone resorption of calcium. PTH. It is probably not

Regulation . serum Ca2+ causes calcitonin secretion. important in normal

calcium homeostasis.

Steroid/thyroid hormone mechanism

The need for gene

transcription and protein

synthesis delays the onset of

action of these hormones.

Steroid/thyroid hormones–

PET CAT:

Progesterone

Estrogen

Testosterone

Cortisol

Aldosterone

Thyroxine and T3

Steroid hormones are lipophilic and insoluble in plasma; therefore, they must circulate

bound to specific binding globulins, which . solubility and allows for . delivery of

steroid to the target organ. . levels of sex hormone-binding globulin (SHBG) lower

free testosterone . gynecomastia. . SHBG raises free testosterone . hirsutism.

HIGH-YI E LD SYSTEMS ENDOCRINE

Binding to enhancerlike

element in DNA

Transformation of

receptor to expose DNAbinding

domain

Binding to receptor

located in nucleus or

in cytoplasm

Cytoplasm

Nucleus

Gene

Pre-mRNA

mRNA

mRNA

Protein

Response

R

H

H Hormone

(Adapted, with permission, from Ganong WF. Review of Medical

Physiology, 20th ed. New York: McGraw-Hill, 2001.)

252

ENDOCRINE-PHYSIOLOGY (continued)

Thyroid hormones Iodine-containing hormones that control the body’s metabolic rate.

(T3/T4)

Source Follicles of thyroid. Most T3 formed in blood. T3 functions–4 B’s:

Function 1. Bone growth (synergism with GH) Brain maturation

2. CNS maturation Bone growth

3. ß-adrenergic effects (. CO, HR, SV, contractility) Beta-adrenergic effects

4. . basal metabolic rate via . Na+/K+ BMR .

ATPase activity = . O2 consumption, RR, Thyroxine-binding globulin

. body temperature (TBG) binds most T3/T4 in

5. . glycogenolysis, gluconeogenesis, lipolysis blood; only free hormone is

Regulation TRH (hypothalamus) stimulates TSH (pituitary), active. . TBG in hepatic

which stimulates follicular cells. Negative failure; . TBG in pregnancy.

feedback by T3 to anterior pituitary . sensitivity

to TRH. TSI, like TSH, stimulates follicular

cells (Graves’ disease).

Insulin-dependent Skeletal muscle and adipose tissue depend on Brain and RBCs depend on

organs insulin for . glucose uptake. Brain and RBCs glucose for metabolism

take up glucose independent of insulin levels under normal

(GLUT-1). circumstances. Brain uses

ketone bodies in starvation.

ENDOCRINE HIGH-YI E LD SYSTEMS

Blood Cell Lumen

Thyroglobulin TG

MIT

I- I2 DIT

T3/T4 T3/T4

Oxidation

Proteolysis

{

253

ENDOCRINE-PATHOLOGY

Cushing’s . cortisol due to a variety of causes. Dexamethasone suppression

syndrome Etiologies include: test:

1. Cushing’s disease (1° pituitary adenoma); . Healthy–. cortisol after low

ACTH dose.

2. 1° adrenal (hyperplasia/neoplasia); . ACTH ACTH-producing tumor–

(see Color Image 68) . cortisol after low dose;

3. Ectopic ACTH production (e.g., small cell lung . cortisol after high dose.

cancer); . ACTH Cortisone-producing

4. Iatrogenic (e.g., chronic steroids); . ACTH tumor–. cortisol after

The clinical picture includes hypertension, weight low and high dose.

gain, moon facies, truncal obesity, buffalo hump,

hyperglycemia (insulin resistance), skin changes

(thinning, striae), osteoporosis, amenorrhea, and

immune suppression (see Color Image 70).

Hyperaldosteronism

Primary (Conn’s Caused by an aldosterone-secreting tumor, resulting Treatment includes

syndrome) in hypertension, hypokalemia, metabolic spironolactone, a K+-sparing

alkalosis, and low plasma renin. diuretic that works by acting

Secondary Due to renal artery stenosis, chronic renal failure, as an aldosterone antagonist.

CHF, cirrhosis, or nephrotic syndrome. Kidney

perception of low intravascular volume results in

an overactive renin-angiotensin system. Therefore,

it is associated with high plasma renin.

Addison’s 1° deficiency of aldosterone and cortisol due to adrenal atrophy, causing hypotension

disease (hyponatremic volume contraction) and skin hyperpigmentation (due to MSH, a byproduct

of . ACTH production from POMC). Characterized by Adrenal Atrophy

and Absence of hormone production; involves All 3 cortical divisions. Distinguish

from 2° insufficiency, which has no skin hyperpigmentation (. pituitary ACTH

production).

Tumors of the adrenal medulla

Pheochromocytoma The most common tumor of the adrenal medulla in Pheochromocytomas may be

adults. Derived from chromaffin cells (arise from associated with

neural crest) (see Color Image 69). neurofibromatosis, MEN types

Neuroblastoma The most common tumor of the adrenal medulla II and III.

in children, but it can occur anywhere along the

sympathetic chain.

HIGH-YI E LD SYSTEMS ENDOCRINE

254

ENDOCRINE-PATHOLOGY (continued)

Pheochromocytoma Most of these tumors secrete epinephrine, NE, Rule of 10’s:

and dopamine. Urinary VMA levels and 10% malignant

plasma catecholamines are elevated. Associated 10% bilateral

with MEN types II and III. Treated with 10% extra-adrenal

a-antagonists, especially phenoxybenzamine, 10% calcify

a nonselective, irreversible a-blocker. 10% kids

Episodic hyperadrenergic symptoms (5 P’s): 10% familial

Pressure (elevated blood pressure) Symptoms occur in “spells”–

Pain (headache) relapse and remit.

Perspiration (tachycardia)

Palpitations

Pallor

Multiple endocrine MEN type I (Wermer’s syndrome)–pancreas MEN I = 3 “P” organs

neoplasias (MEN) (e.g., Zollinger-Ellison syndrome, insulinomas, (Pancreas, Pituitary, and

VIPomas), parathyroid, and pituitary tumors. Parathyroid).

Presents with kidney stones and stomach ulcers. All MEN syndromes have

MEN type II (Sipple’s syndrome)–medullary autosomal-dominant

carcinoma of the thyroid, pheochromocytoma, inheritance.

parathyroid tumor. Associated with ret gene in

MEN type III (formerly MEN IIb)–medullary MEN types II and III.

carcinoma of the thyroid, pheochromocytoma,

and oral and intestinal ganglioneuromatosis

(mucosal neuromas).

Hypothyroidism and hyperthyroidism

Hypothyroidism Cold intolerance, hypoactivity, weight gain, fatigue, . TSH (sensitive test for 1°

lethargy, . appetite, constipation, weakness, hypothyroidism), . total

. reflexes, myxedema (facial/periorbital), dry, T4, . free T4, . T3 uptake.

cool skin, and coarse, brittle hair. Riedel’s thyroiditis–thyroid

Hyperthyroidism Heat intolerance, hyperactivity, weight loss, chest replaced by fibrous tissue

pain/palpitations, arrhythmias, diarrhea, . (hypothyroid).

reflexes, warm, moist skin, and fine hair. . TSH (if 1°), . total T4,

Graves’ disease An autoimmune hyperthyroidism with thyroid- . free T4, . T3 uptake.

stimulating/TSH receptor antibodies. Graves’ is a type II

Ophthalmopathy (proptosis, EOM swelling), hypersensitivity.

pretibial myxedema, diffuse goiter. Often

presents during stress (e.g., childbirth) (see Color

Image 71).

Hashimoto’s Autoimmune disorder resulting in hypothyroidism. Slow course; moderately enlarged,

thyroiditis nontender thyroid. Lymphocytic infiltrate with germinal centers. Antimicrosomal

and antithyroglobulin antibodies.

Subacute Self-limited hypothyroidism often following a flulike May be hyperthyroid early in

thyroiditis illness. Elevated ESR, jaw pain, early course.

(de Quervain’s) inflammation, and very tender thyroid gland.

ENDOCRINE HIGH-YI E LD SYSTEMS

255

Thyroid cancer 1. Papillary carcinoma–most common, excellent prognosis, “ground-glass” nuclei,

psammoma bodies.

2. Follicular carcinoma–good prognosis, uniform follicles.

3. Medullary carcinoma–from parafollicular “C cells”; produces calcitonin, sheets of cells

in amyloid stroma. MEN types II and III.

4. Undifferentiated/anaplastic–older patients, very poor prognosis.

Cretinism Endemic cretinism occurs wherever endemic goiter Cretin means Christlike

is prevalent (lack of dietary iodine); sporadic (French chrétien). Those

cretinism is caused by defect in T4 formation or affected were considered so

developmental failure in thyroid formation. mentally retarded as to be

Findings: pot-bellied, pale, puffy-faced child with incapable of sinning. Still

protruding umbilicus and protuberant tongue. common in China.

Acromegaly Excess GH in adults. Findings: large tongue with . GH is normal in stress,

deep furrows, deep voice, large hands and feet, exercise, and hypoglycemia.

coarse facial features, impaired glucose tolerance

(insulin resistance). . GH in children .

gigantism. Treat medically with octreotide.

Hyperparathyroidism

Primary Usually an adenoma. Hypercalcemia, hypercalciuria Osteitis fibrosa cystica (von

(renal stones), hypophosphatemia, . PTH, . cAMP Recklinghausen’s

in urine. Often asymptomatic, or may present syndrome)–cystic bone

with weakness and constipation (“groans”). spaces filled with brown

fibrous tissue (bone pain).

Secondary 2° hyperplasia due to . serum Ca2+, most often in Renal osteodystrophy–bone

chronic renal disease. Hypocalcemia, lesions due to 2°

hyperphosphatemia, . PTH. hyperparathyroidism due in

turn to renal disease.

“Stones, bones, and groans.”

Hypoparathy- Hypocalcemia, tetany. Due to accidental surgical Pseudohypoparathyroidism–

roidism excision (thyroid surgery) or DiGeorge syndrome. autosomal-recessive kidney

Chvostek’s sign–tap facial nerve . contraction of unresponsiveness to PTH.

facial muscles. Hypocalcemia, shortened

Trousseau’s sign–occlusion of brachial artery with 4th/5th digits, short stature.

BP cuff . carpal spasm.

Hypercalcemia Caused by Calcium ingestion (milk-alkali syndrome), CHIMPANZEES.

Hyperparathyroid, Hyperthyroid, Iatrogenic

(thiazides), Multiple myeloma, Paget’s disease,

Addison’s disease, Neoplasms, Zollinger-Ellison

syndrome, Excess vitamin D, Excess vitamin A,

Sarcoidosis.

HIGH-YI E LD SYSTEMS ENDOCRINE

256

ENDOCRINE-PATHOLOGY (continued)

Diabetes mellitus

Acute manifestations Polydipsia, polyuria, polyphagia, weight loss, DKA (type 1), hyperosmolar coma (type 2),

unopposed secretion of GH and epinephrine (exacerbating hyperglycemia).

Chronic Nonenzymatic glycosylation:

manifestations 1. Small vessel disease (diffuse thickening of basement membrane) . retinopathy

(hemorrhage, exudates, microaneurysms, vessel proliferation), glaucoma,

nephropathy (nodular sclerosis, progressive proteinuria, chronic renal failure,

arteriosclerosis leading to hypertension)

2. Large vessel atherosclerosis, CAD, peripheral vascular occlusive disease and

gangrene, cerebrovascular disease

Osmotic damage:

1. Neuropathy (motor, sensory, and autonomic degeneration)

2. Cataracts (sorbitol accumulation)

Tests Fasting serum glucose, glucose tolerance test, HbA1c (measures long-term diabetic control).

Type 1 vs. type 2 diabetes mellitus

Type 1–juvenile onset Type 2–adult onset

Variable (IDDM) (NIDDM)

1° defect Viral or immune destruction of ß cells . resistance to insulin

(see Color Image 67)

Insulin necessary in treatment Always Sometimes

Age (exceptions commonly occur) < 30 > 40

Association with obesity No Yes

Genetic predisposition Weak, polygenic Strong, polygenic

Association with HLA system Yes (HLA-DR3 and 4) No

Glucose intolerance Severe Mild to moderate

Ketoacidosis Common Rare

ß-cell numbers in the islets . Variable

Serum insulin level . Variable

Classic symptoms of polyuria, Common Sometimes

polydipsia, thirst, weight loss

ENDOCRINE HIGH-YI E LD SYSTEMS

Increased plasma

amino acids,

nitrogen loss in

urine

Increased protein

catabolism

Insulin deficiency (and glucagon excess)

Decreased glucose

uptake

Hyperglycemia,

glycosuria,

osmotic diuresis,

electrolyte depletion

Increased

lipolysis

Increased plasma FFAs,

ketogenesis, ketonuria,

ketonemia

Dehydration,

acidosis

Coma,

death

257

Diabetic One of the most important complications of type 1 diabetes. Usually due to an . in

ketoacidosis insulin requirements from an . in stress (e.g., infection). Excess fat breakdown and .

ketogenesis from the . in free fatty acids, which are then made into ketone

bodies.

Signs/symptoms Kussmaul respirations (rapid/deep breathing), hyperthermia, nausea/vomiting, abdominal

pain, psychosis/dementia, dehydration. Fruity breath odor (due to exhaled acetone).

Labs Hyperglycemia, . H+, . HCO3

– (anion gap metabolic acidosis), . blood ketone levels,

leukocytosis. Hyperkalemia, but depleted intracellular K+.

Complications Life-threatening mucormycosis, Rhizopus infection, cerebral edema, cardiac arrhythmias,

heart failure.

Treatment Fluids, insulin, and potassium; glucose if necessary to prevent hypoglycemia.

Diabetes insipidus Characterized by intensive thirst and polyuria together with an inability to concentrate

urine owing to lack of ADH (central DI–pituitary tumor, trauma, surgery,

histiocytosis X) or to a lack of renal response to ADH (nephrogenic DI–hereditary or

2° to hypercalcemia, lithium, demeclocycline).

Diagnosis Water deprivation test–urine osmolality doesn’t ..

Findings Urine specific gravity < 1.006; serum osmolality > 290 mOsm/L.

Treatment Adequate fluid intake. For central DI–intranasal desmopressin (ADH analog). For

nephrogenic DI–hydrochlorothiazide, indomethacin, or amiloride.

SIADH Syndrome of inappropriate antidiuretic hormone Causes include:

secretion: 1. Ectopic ADH (small cell

1. Excessive water retention lung cancer)

2. Hyponatremia 2. CNS disorders/head

3. Urine osmolarity > serum osmolarity trauma

Very low serum sodium levels can lead to seizures 3. Pulmonary disease

(correct slowly). 4. Drugs (e.g.,

Treat with demeclocycline or H2O restriction. cyclophosphamide)

Carcinoid Rare syndrome caused by carcinoid tumors Rule of 1/3s:

syndrome (neuroendocrine cells), especially metastatic 1/3 metastasize

small bowel tumors, which secrete high levels of 1/3 present with 2nd

serotonin (5-HT). Not seen if tumor is limited to malignancy

GI tract (5-HT undergoes first-pass metabolism in 1/3 multiple

liver). Results in recurrent diarrhea, cutaneous Derived from neuroendocrine

flushing, asthmatic wheezing, and right-sided cells of GI tract.

valvular disease. Most common tumor of Treat with octreotide.

appendix. . 5-HIAA in urine.

Zollinger-Ellison Gastrin-secreting tumor of pancreas or duodenum. Causes recurrent ulcers. May be

syndrome associated with MEN type I.

HIGH-YI E LD SYSTEMS ENDOCRINE

258

ENDOCRINE-PHARMACOLOGY

Diabetes drugs Treatment strategy for type 1 DM–low-sugar diet, insulin replacement.

Treatment strategy for type 2 DM–dietary modification and exercise for weight loss;

oral hypoglycemics.

Orlistat

Mechanism Alters fat metabolism by inhibiting pancreatic lipases.

Clinical use Long-term obesity management (in conjunction with modified diet).

Toxicity Steatorrhea, GI discomfort, reduced absorption of fat-soluble vitamins, headache.

Sibutramine

Mechanism Sympathomimetic serotonin and norepinephrine reuptake inhibitor.

Clinical use Short-term and long-term obesity management.

Toxicity Hypertension and tachycardia.

ENDOCRINE HIGH-YI E LD SYSTEMS

Drug Classes Action Clinical Use Toxicities

Insulin:

Lispro (short-acting) Binds insulin receptor Type 1 DM. Hypoglycemia,

Insulin (short-acting) (tyrosine kinase activity). Also life-threatening hypersensitivity

NPH (intermediate) Liver: . glucose stored as hyperkalemia and reaction (very

Lente (long-acting) glycogen. stress-induced rare).

Ultralente Muscle: . glycogen and hyperglycemia.

(long-acting) protein synthesis, K+

uptake.

Fat: aids TG storage.

Sulfonylureas: Close K+ channel in Stimulate release of First generation:

First generation: ß-cell membrane, so endogenous insulin in disulfiram-like

Tolbutamide cell depolarizes . type 2 DM. Require effects.

Chlorpropamide triggering of insulin some islet function, Second generation:

Second generation: release via . Ca2+ influx. so useless in type 1 DM. hypoglycemia.

Glyburide

Glimepiride

Glipizide

Biguanides: Exact mechanism is Used as oral hypoglycemic. Most grave

Metformin unknown. Possibly . Can be used in patients adverse effect

gluconeogenesis, . without islet function. is lactic acidosis.

glycolysis, . serum

glucose levels.

Glitazones: . target cell response to Used as monotherapy in Weight gain.

Pioglitazone insulin. type 2 DM or combined Hepatotoxicity

Rosiglitazone with above agents. (troglitazone-

no longer used).

a-glucosidase inhibitors: Inhibit intestinal brush Used as monotherapy in GI disturbances.

Acarbose border a-glucosidases. type 2 DM in combination

Miglitol Delayed sugar hydrolysis with above agents.

and glucose absorption

lead to . postprandial

hyperglycemia.

259

Propylthiouracil, methimazole

Mechanism Inhibit organification and coupling of thyroid hormone synthesis. Propylthiouracil also

. peripheral conversion of T4 to T3.

Clinical use Hyperthyroidism.

Toxicity Skin rash, agranulocytosis (rare), aplastic anemia.

Other hypothalamic/pituitary drugs

Drug Clinical use

GH (somatostatin) GH deficiency, Turner’s syndrome

Octreotide Acromegaly, carcinoid, gastrinoma, glucagonoma

Oxytocin Stimulates labor, uterine contractions, milk let-down; controls uterine hemorrhage

Desmopressin (ADH) Pituitary (central, not nephrogenic) DI

Levothyroxine, triiodothyronine

Mechanism Thyroxine replacement.

Clinical use Hypothyroidism, myxedema.

Toxicity Tachycardia, heat intolerance, tremors.

Glucocorticoids Hydrocortisone, prednisone, triamcinolone, dexamethasone, beclomethasone.

Mechanism . the production of leukotrienes and prostaglandins by inhibiting phospholipase A2

and expression of COX-2.

Clinical use Addison’s disease, inflammation, immune suppression, asthma.

Toxicity Iatrogenic Cushing’s syndrome–buffalo hump, moon facies, truncal obesity, muscle

wasting, thin skin, easy bruisability, osteoporosis, adrenocortical atrophy, peptic

ulcers.

HIGH-YI E LD SYSTEMS ENDOCRINE

260 ENDOCRINE HIGH-YI E LD SYSTEMS

NOTES

High-Yield Clinical

Vignettes

Anatomy

Physiology

Pathology

Pharmacology

H I G H -Y I E L D S Y S T E M S

Gastrointestinal

261

“I have flabby thighs, but fortunately my stomach covers them.”

–Joan Rivers

“You thing of no bowels!”

–Shakespearean insult

262

GASTROINTESTINAL-HIGH-YIELD CLINICAL VIGNETTES

Baby vomits milk when fed and What kind of fistula is Blind esophagus with lower

has a gastric air bubble. present? segment of esophagus attached

to trachea.

After a stressful life event, What is the diagnosis? Crohn’s.

30-year-old man has diarrhea

and blood per rectum;

intestinal biopsy shows

transmural inflammation.

Young man presents with mental What treatment should Penicillamine for Wilson’s

deterioration and tremors. He he receive? disease.

has brown pigmentation in a

ring around the periphery of his

cornea and altered LFTs.

20-year-old male presents with What is the most Gilbert’s disease.

idiopathic hyperbilirubinemia. common cause?

GASTROINTESTINAL HIGH-YI E LD SYSTEMS

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