Via BPT

Week 3 Notes

3A Drugs that affect Cardiac Rhythm Class Name Prototype Drug Defining electrophysiologic effects TargetsIA Local

anestheticProcainamide Depress Fast response excitability and increase APD;

block Ik, these prolong AP INa, IK

IB Lidocaine Depress fast response excitability especially in depolarized tissue

INa

IC Flecainide Depress fast response excitability in normal and depolarized tissue

INa

II Beta blocker Atenolol Block beta adrenergic effects B receptor (ICa, IK, If)

III Class III Dofetilide Prolong APD without depressing excitability in fast response tissue

Ik (no Ina)

IV Ca channel blockers

Verapamil Depress conduction and excitability in slow response tissue (AV node, SA node)

ICa

Drugs that target K and Na channels would affect ventricular myocardium (muscle excitation) while drugs that affect Ca would affect AV and SA (pacemaker cells); But for AV reentry, need combo so both kinds of drugs may be used

A. Types of Arrhtymias treated a. Automaticity

Phase 4 depolarizationb. Reentrant tachycardias

excitability and ERP c. Triggered activity/Tachycardia due to EAD (Torsades des pointes)

action potential duration in ventricle most important B. Differences between slow and fast conducting tissue

a. Effective Refractory Period in slow >> in fast b. Slow dependent on Icac. Fast dependent on Ik (only the length of the depolarization)

C. K channel blockers a. Prolong conduction time by slowing repolarization; (not

enough effect to slow depolarization)b. Activity enhanced with

i. Slow HR (also with prolonged depolarization of AP as in TdP)

ii. HypoKiii. HypoMg

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S-VW Class Drug Channels blocked Effects on Cond. Vel.& excitability(Ex) ERP APDIB Lidocaine Na Decrease variableIA Procainamid

eNa, K Decrease Increase Increase

IC Flecainede Na Decrease variableIII Dofetilide K No change Increase Increase

D. Na Channel Blockers a. Fewer channels available but b. Potency: 1B (lidocaine) < IA < ICc. Activity enhanced with

i. affinity to inactivated channels ii. potency with depolarized RMP cells

iii. potency w/ fast HR E. Slow Response Tissue Drugs

a. PSN stimulation works by 2 pathways i. MACh activity antagonizes SNS by activing Gi

and inhibiting effects of Gsii. IkACH (SA and AV node only) hyperpolarizes,

prolonged refractory period b. Adenosin-R have same electrophysiological properties as

muscarinic-R i. Also Gi and IkACH

c. ALL of these drugs ↓AVN excitatbility (risk for AV block)

S V-W

Class

Drug Target Main ion channel effect

Affects on sinus rate

Effects on AVN ERP

Effects on AVN excitability

II Atenolol Β-R blocker ↓ICa Decrease Increase DecreaseIV Verapamil Direct Ca-ch

blocker↓ICa Decrease Increase Decrease

Digoxin Vagal N Mus-R ↓ICa, IKAch Decrease Increase DecreaseAdenosine Adenosine-R

agonist↓ICa, IKAch Decrease Increase Decrease

F. Tachycardias due to Reentry a. Fixed circuit

i. V-tach in healed MIii. AV nodeal reentrant tach

iii. AV reentry w/ bypass tract b. Multiple shifting waves

i. A-fibii. V-fib

G. MoA anti-arythmatic drugs

H. The same Drugs can promote reentry or cause conduction block a. Length dependent mechanisms; don’t know how much drug is

needed

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Electrophysiologic Effect Antiarrhythmic Mechanism.Decrease excitabilityClass I drugs

Fixed bidirectional block Prohibit transmission of the wave by making permanent block

ERPClass IA or III drugs

Block due to refractoriness Wave will then hit refractory tissue

Two mechanisms by which drugs cause blockTherapeutic strategy Class Necessary substrate Risk1.Prolong ERP to cause refractory block

IA, III Short excitable gap in the circuit

Excessively long APD, EADs

2.Depress excitability to cause fixed block

IA, IB, IC Low safety factor Slow conduction, facilitates reentry

I. Drugs to treat AV reentrant tachycardia (bypass tract)

Procainamide/sotalaol for BPTOthers for AV Node

J. Drugs to treat post-MI reentry

)

K. Drug to treat AV nodal reentry

L. Drug to treat multiple wavelet reentry “A-fib”a. Etiology: enlarged LA (more space for multiple

wavelet formation)b. Need to treat both atrial muscle activation AND

prolonged AV nodal ERP

M. Drug to treat Torsades des Pointes (TdPa. Excessive prolongation of activated K channels; Class

IA and III, hypoK and hypoMgb. Polymorphic wavesc. May be

N. Drugs used in cardiology that might TRIGGER arrhythmias

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O.

P. Conditions that make using antiarrhythmic drugs riskier to use Torsades

Week 3E RAAS and Hypertension

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Long QT (esp with hypoK,Mg) Long QT (esp with hypoK,Mg)

DofetilideAmiodarone BL

Drug Channels Receptors Pump

SVW Class

Na K Ca α β M2 P Na-K

Med Fast Slow

Procainamide BL BL IAQuinidine BL BL A

nAn IA

Lidocaine BL IBFlecainide BL ICAtenolol An IIDofetilide BL IIIAmiodarone BL BL BL A

nAn III

Sotalol BL An IIIVerapamil BL IVAtropine AnDigoxin Ag BL Note

effect on

Adenosine Ag

Key points: a. ATII is the most potent VASOCONSTRICTOR GEN IN VIVO!

BUT IT IS CRItiCAL FOR MeAINING SVR tone In inflammation

ATII NfKB VCAMII, MCP1, IL6 (CRP)Renal constriction Adrenal Cortex (ALD)Adrenal Medulla (Catecholamines)

ATII-Rs have equal affinity for ATII

AT1 vascular sm muscle, kidney, ad cortex, pituitary

vasoconstriction aldosterone release cell propliferation, hypertrophy, matrix deposition

AT2 uterus, High in fetus/but inducible vasodilation NO, Bradykinin, cGMP release

antipropliferative, apoptosis

RENIN is turned on by HypovolemiaHyponatremia Hypotension

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Adrenergic stimulation

renin – rate limiting step in angiotensin II formation secretion controlled by:

o ↓ renal perfusion (↓BP)o ↓ [Na+]o sympathetic activation

angiotensinogen – produced in the liverACE – nonspecific (cleaves dipeptides from many substrates)angiotensin I – little biological activityangiotensin II – most biological activityangiotensin III – some activity, more tissue-specificangiotensinases – inactivate angiotensins, non-specific

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ATI sensitive to Losartan VSMC kidney brain adrenal ctx pituitary PLA2, PGs, etc.

AT2 (inducible) uterus brain highest in fetus

The renin-angiotensin system appears to play a major role in the pathogenesis of HTN even when plasma renin activity is not elevated.adrenal ctx ↑ aldosterone (↑↑↑ in hyponatremia, hyperkalemia)kidney antidiuretic, antinatriuretic

↓ glomerular filtrationCV direct vasoconstrictor on VSMCs ↑BP

↑ inotropy w/ little change in HR (via baroreceptor)peripheral ANS

sympathetic: ↑NE, ↑ sensitivity of tissues adrenal medulla catecholamine release

CNS central pressor response ↑ADH, ACTH thirst and sodium appetite

Effects of Aldosterone: Na+ retention K+/Mg++ loss baroreceptor dysfxn impaired arterial compliance prevention of myocardial NE uptake regulation of sodium transport in colon, sweat glands, and salivary glands

Week 3C Hypertension I. HTN is a syndrome of arterial pressure dysregulation

a. primary – no recognized underlying disease (94%)b. secondary – underlying disease usually renal (6%)c. benign – mild w/ slow progression (95%) “Silent Killer”

(1) CHF(2) MI(3) Stroke

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AldosteroneSecretion

Na+ Depletion

Blood VolumeFalls

Blood PressureFalls

RENINRELEASE

Blood PressureRises

Blood VolumeRises

Na+ Retention

ANGIOTENSINFORMATION

Vasocontriction

inhibits stimulates- +

(4) Chronic renal failure (5) Subsequence malignant HTN

d. malignant – severe, rapid progress (5%)1. Lower is Always Better!2. BP = CO X SVR (CO is usually nl in HTN, SVR is dysregulated)

II. Physiologic Consequencesa. LVHb. ↑ stress on elastic and muscular aa ( aneurysms, atherosclerosis)c. obliteration of systemic arteriolesd. generalized deposition of collagene. pronounced arteriolar destruction of the kidney

III. Mechanisms that protect against HTN are inhibited in chronic HTN1. BaroR Reflex

a. fast responseb. ↑ pressure stretch receptors brain ↓ pressure

(i) baroreceptors are reset to a higher pressure -- permissive2. Pressure-Natriuresis

a. ↑ renal art pressure lose Na+/fluid ↓ blood volume ↓BP

(i) in HTN this is permissive or overwhelmed(ii) “R” vs “S” rats (iii) Rice Diets

3. Renin-Angiotensin-Aldosterone Axisa. ↑ bp ↓ renin normally (to vasodilate)

(i) in HTN this is either etiologic or permissiveIV. Epidemiology

1. heredity – black>white, familial (largely b/c of differences in Na excretion)

2. sodium3. stress -- ↑ SNS; (causes VC less so that nrm4. obesity5. EtOH

The “Vicious Cycle”underlying causes initial effects subsequent events consequencesgeneticNa+behavior

↑ total body Na+↑SVR

destruction of systemic arteriolesloss of renal fxn

↑↑SVR↓↓ renal fxn↑↑CV loadventricular remodeling

Circulating natriuretic hormone release of natriuretic hormone ↓Na/K+ pump, [Na i]Na/Ca exchange SVRf

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V. Vascular changes in HTN:1. acceleration of existing processes (See with any HTN; due to aging, diabetes, etc)

a. atherosclerosisb. hyaline atherosclerosis (also in

diabetes; deposition of plasma proteins due to endothelial leakage)

2. unique to HTNa. adaptive

(a) vasoconstriction (b) medial hypertrophy(c) fibroelastic intimal

hyperplasiab. destructive changes (only in malignant HTN)

(a) fibrinoid necrosis (i) of the endothelium and smooth muscle(ii) ATII (induce and also proliferative) (iii) Deposition of fibrin

1. microangiopathic hemolytic anemia 2º/2 fibrin2. produce shistocytes by forcing RBCs to go through mesh

(b) hyperplastic arteriolitis – onion skinning(i) concentric prolif of SMC and interstitial proteoglycans

3. Reversibility a. Reversible

(a) functional and SOME structural changes (i) vasoconstriction(ii) medial hypertrophy

b. Irreversible (a) Some structural

(i) Arterial fibroelastic intimal hyperplasia (ii) Hyaline ateriolosclrosis (iii) Advanced atherosclerosis

(b) THESE CHANGES CAUSE FIXED INCREASES IN BP

Benign HTN Malignant HTN Asymptomatic, risk w/ age DBP > 90 OR SBP > 140 Clinically silent until late in course

1. 35-50 yo, smokers, AAs, M>F, ↓socioeco2. Untxed 1yr mortality = 90%; txed 5yr mortality =

25%

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structural changes/damage to tissues progression to MALIGNANT

(1) CHF(2) MI(3) Stroke(4) Chronic renal failure (5) Subsequence malignant HTN

organ effects:1. cardiac: LVH w/o dilation [concentric]

ischemia, angina, CHFa. myofibrils, metabolic rate, energy needs b. Arteries compromised, ↓blood flow, ischemia,

fibrosis c. ↓compliance of LV, impaired diastolic filling and

systolic contractility 2. renal:

a. granular surface, vascular changes, fibrosis b. benign nephroateriosclerosis: microv. Dz w/

glomerular scarring and tubular atrophy (gradually wither away instead of acute necrosis)

c. ↓GFR, Na excretiond. Activates RAASe. ↓urodilatin (or some renally secreted natriuretic

factor) chronic renal failure

3. cerebral: microaneurysms (dilations) in eye microaneurysms and ↑ atherosclerosis

ischemic infarct microaneurysms hemorrhagic infarct ICH lacunae = cystic mini-infarct Berry aneurysms SAH

3. DBP > 120 (SBP>210)4. Lethal if not treated5. USUALLY Symptomatic

a. scotoma (eyes), retinal hemorrahge, exudates

b. N/V, headache (↑ICP), HTN encephalopathy

c. hematuria (↓renal fxn)6. PE: papilledema, retinal hemorrhage/exudate7. Lab: ↓ renal fxn, proteinuria/hematuria,

microangiopathic hemolytic anemia, ↑ renin, ATII, ald

8. Causes of Death:a. (Chronic) renal failure + ( acute)

cortical necrosis 20%b. (acute) Stroke/CVA 15%c. (acute) CAD 10%d. acute/chronic CHF 26%

primary no recognized underlying disease (94%)

Secondary HTN (known cause)A. secondary – underlying disease usually renal

or adrenal(6%)a. kidney: RAAS chronic renal disease,

renovascular disease, aortic coarctation; renoprival (medullary destruction), urodilatin

Note the asymmetry here compared to symmetric in hyaline nephrosclerosis

b. adrenal: córtex: 1o ALD,

(Conn’s), 1o

CRT(Cushing’s), diffuse Cort hyperplasia (medulla) pheochromocytoma

c. CNS: tumor, ↑ICPd. Drugs: OCP, EtOHe. Pregnancy (preelampsia): placental

antiangiogenic substance

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Resistance HTNA. Etiology: Abn regulation of vascular resistance B. Sx:

1. SVR2. SBP,DBP, and MAP3. Slightly PP4. Typical BP: 150/100

C.

Compliance HTNA. Etiology: ↓ great vessel compliance (stiff pipes) B. Sx:

1. Nrml/mod in SVR2. SBP, --DBP, slightlyMAP3. PP4. Typical BP: 170/60

C. Consequences: 1. Severe LV pressure

↓LV diastolic compliance Diastolic HF

2. Accelerated vascular disease Aortic aneuryms CVD

D.

Week 3L Antihypertensive Therapeutics I. Pathophysiology of HTN

a. BP = CO (=SVxHR) x SVR (PVRxRVR)II. Diuretics: Thiazides

a. MoA: Diuretic, naturetic, Kalluretici. ↓ Na absorption in distal convulated tubules

ii. NaCl active cotransporter in apical cell membrane (which absorpbs 5-8% of filtrate)b. Compensatory response:↓Na and ↓H2O with it

i. BUT ↓plasmia V RAAS ↓K and Na distal H2O reabsorption c. PK

i. Renal excretion (↓dose in elderly)ii. Duration of action: 24hrs (LONG)

d. Response rate i. Best in AAs and elderly

ii. Depends on vigor of compensatory process iii. ↓ in chronic renal insufficiency

e. Toxicities/countraindications i. Sulfa allergy

ii. ↓Kiii. Insulin resistance (

III. CaChannel Antagonists (CCBs) a. MOA:↓Ca influx into

i. vascular smooth muscle: Nifedipine>Verapamil>>diltiazem1. binds calmodulin during resting state, activating MLCK to myosin-PO4 and muscle

activation to maintain basal tone a. ↓contractility b. Dihydropyridine >> hydropyridine

ii. Cardiac muscle: VERAPAMIL>Diltiazam>Nifedipine

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1. Atrial/Ventricular myocytes: Ca-induced Ca release from SR Ca binds tropinin, removing tropomyosin’s block of actin/myosin binding

a. ↓contractility and O2 demand b. coronary vasodilation

USE for PSVT concomitant w/ HTN and angina 2. SA/AV node: T and L type Ca channel spontaneous phase 4 depolarization

a. ↓HR and intracardiac conductivity b. Channel types:

i. L is on ALL muscle cells ii. CCAs (majority) affect ONLY L type

c. Classi. Non-dihyropyridine: bind when channel is open ie. in ACTIVE TISSUE (blockade in tissue w/

stimulation)1. Verapamil2. Diltiazem

ii. Dihydropyridine: bind during resting state 1. Nifedipine 2. Amlodipine (most prescribed anti-HTN drug)

d. Verapamil i. MOA: ↓cardiac contractility, blood flow, and

conductivity ii. Indications: PSVT, angina, HTN (↓SVR)

iii. SE: constipation e. Diltiazem

i. ↓est incidence of SEs ii. Indications: SVT , but NOT effective in HTN

f. Nifedipine i. MoA: ↓↓PROFOUND Peripheral vasodilatory Effects

ii. Indications: HTN, used with βblocker to PREVENT reflex Tachycardia iii. COUNTRAindications: postMI, CHFiv. SEs: face flushing, headaches, dizziness, palpitations, ankle swelling

IV. Inhibition of RAASa. ACE-I b. ARBs c. Direct Inhibitor of Renind. Best in ComboRx

V. Peripheral Vasodilators a. MOA:

i. Directly relax vascular SMCsii. Direct = NOT dependent on innervations and not mediated by known receptors

b. Arterial: hydralazine, minoxidilc. Venous: nitrates d. Both A/V: Nitroprusside e. Hydralazine

i. Acts on Renal, Peripheral, splanchnic, and coronary arteries ii. ↓PVR ↓BP

iii. Indications: 1. HTN during pregnancy during preeclampsia

iv. Toxitcitiy: 1. reflex tach use in combo with β-blocker2. Excessive vasodilation: flusing, sweating, palpitations, hypotension, angina

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3. SLE-like syndrome (arthralgias, myalgia, fever, and rash, slow acetylators) f. Minoxidil

i. Activates ATP-modulated K channel in arteries HYPERpolarization and relaxation ii. MoA: Direct arteriolar vasodilation, ↓PVR and BP

1. Compensatory response: Reflex SNS activation Na and RAAS reflex tach use in combo with β-blocker

iii. SE: hair growthg. Nitroprusside

i. MOA: metabolized by SMC into NO activate gunaylate cyclase ii. cGMP relaxation of SMC and vasodilation

iii. Acts on both A and V to ↓PVR (afterload) and venous return (preload) iv. Delivery: in complex with Fe, cyanide, and nitrosamine groups

1. RBC liberate cyanide by metabolizing complex 2. Sodium thiosulfate added to solution to ↓risk of cyanide toxicity (can cause actue

neurological events) 3. Unstable in daylight

v. Indications: HTN crises, RAPID action (1-2min) by infusion, consistent response VI. Sympatholytics for HTN

a. β-Blockers b. peripheral α1, α2 antagonists c. Central α2 agonists

i. Target preganglionic α2-Rs on adrenergic neurons in admedulla

ii. ↓SNS outflow, UNOPPOSED vagal tone iii. ↓PVR, HR, CO, and BPiv. Methyldopa (SEfx: CNS) v. Clonidine (Available as transdermal patch, non-CNS)

vi. SNS: unopposed vagal tone d. Adrenergic neurotransmitter release blockers

1. Reserpine (depletes peripheral NE from storage vesicles in SNS endings, ↓PVR)

a. SEFX: DEPRESSION2. Guanethidine

a. ↓release of Ne from peripheral SNS endings

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1 LEARN THIS

Fusiform

Week 3G Aneuryms

A. Aneurysms = localized dilation of a blood vessel, usually art a. Saccular vs. fusiform

i. size = risk of ruptureb. True aneurysms

i. Berry (Saccular) 1. saccular aneurysms of cerebral aa

ii. atherosclrotic (aortic most impo)1. most freq. in abdominal aorta (AAA)2. weakening of internal elastic media

iii. Syphylitic c. Dissecting hematoma

B. Physiology of aneurysms a. cause sxs by:

i. mass effectii. distal thrombus embolization

iii. rupture + hemorrhageb. LaPlace Law R, P, ↓W causes Wall Tension and risk of rupture

a. etiology1. berry – 2. atherosclerotic aneurysms – 3. syphilitic

C. Dissection –a. focal destruction of elastica and accumulation of extracellular mucopolysaccharide in cystic spaces =

cystic medial necrosis (misnomer)b. Structural weakening of wall of artery “medial degernation” elastic fibers destroyed c. HTNd. Seen in MARFAN’s (defect in TGF-β R, TypeIII collage)e. HTN speeds up tearing of intimal layer hematoma that can actually reenter lumen as “double barrel”f. Sx:

“tearing” migratory chest pain ant to post chest to back to abd lose upper extremity pulses (eg. Right radial, Coroanary art, Carotid ar, mesenteryc) occlusion

of aortic branches (, CVA, MI) cardiac tamponade, pleura, peritoneal hematoma rupture/exsanguinations into cavity

g. Pathophysiology:1) Initiated by rupture of vasa vasorum in weakend media

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2) Variable extension in either direction3) Exit site (most often above aortic valve) 4) Possible distal reentry site distally 5) Possible hemorrhage outside wall

Thinning of the media as the aneurysm pushes out, thinning the wall and risk of rupture

Week 1P Cardiovascular Effects of Autonomic Antagonists I. PSN antagonists

1) ↓HR, AV nodal conduction BRADYCARDIA 2) ↓SAR DECREASED SAP

e. Atropine i. No efx on CNS

ii. Indications: HR, ↓AV nodal refractoriness, ↓PSN Systemic arteriolar vasodilation

iii. Prevents “vagal reactioniv. Restore AV conduction in conductions that prolong

AV nodal refractoriness (Inferiror wall MI, dig tox) f. Scopolamine

i. CNS (NOT used in CV)II. SNS antagonists

a. SNS-blockers: 2) CARDIAC

1. ↓impulse formation (HR)2. ↓conduction (refractoriness, ↓velocity)3. ↓Inotropy, ↓metabolic rate 4. ↓renin release

3) Vascular SMCs: 1. Arteriolar vasodilation 2. Venodilation

2) A-blockers 1. Prazosin a1>>a22. Doxazosin, Terazosin PURE a13. Terazosin also for BPH4. MOA: A and V dilation LOWER PVR 5. Indication: 3rd line HTN, not as effective, do not improve mortality, 6. SE: postural hypotension

3) B-blockers 1. Considerations :

1. Selectivity of b1 avoid nonselective drugs in ppl w/ pulmonary conditions (ie. COPD, asthma)

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2. Sympathomimetic activity (ppl w. ANGINA) 3. Lipid solubility (CNS SEfxs)4. Duration of action

2. MOA: 1. ↓HR, conduction, contractility

3. Indications CHF, CV ischemia, arrhythmia, HTN

4. SEE DRUGS CHART FOR DETAILS 5. KEY POINT re combined blockers Labetolol

and carvedilol 1. MoA

a. Α1 receptor antagonism (vasoDilation and ↓PVR

b. NONSELECTIVE β blockade i. ↓HR and Renin

release III. Management

1) Chronic CHF (β-blocker)2) Actue cardiogenic shock (inotrope)3) MI immediately afterwards(β-blocker)4) Complete heart block (NO β-blocker)5) Angina (β-blocker)

IV. Ischemia 1) O2 supply determined by

1. Blood O2 level1. ↓in anemia/hypoxia

2. Coronary perfusion at rest and flow reserve (can arteries dilate on demand, depends on endocardial perfusion during diastole, which is regulated by diastolic pressure and duration)

1. ↓in atherosclerosis, thrombosis, vasospasm2. ↓HTN and tachycardia (b/c depends on

2) Place for β-blockers in ischemia 1. ↓HR, T in diastole,perfusion 2. ↓O2 demand (↓HR and contractility) , ↓SNS reflex, ↓double product?, ↓BP

VASOACTIVE PEPTIDES AND INHIBITORS

renin – rate limiting step in angiotensin II formation secretion controlled by:

o ↓ renal perfusion (↓BP)o ↓ [Na+]o sympathetic activation

angiotensinogen – produced in the liverACE – nonspecific (cleaves dipeptides from many substrates)

angiotensin I – little biological activityangiotensin II – most biological activityangiotensin III – some activity, more tissue-specificangiotensinases – inactivate angiotensins, non-specific

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2 Why carvedilol is best

AldosteroneSecretion

Na+ Depletion

Blood VolumeFalls

Blood PressureFalls

RENINRELEASE

Blood PressureRises

Blood VolumeRises

Na+ Retention

ANGIOTENSINFORMATION

Vasocontriction

inhibits stimulates- +

The renin-angiotensin system appears to play a major role in the pathogenesis of HTN even when plasma renin activity is not elevated.adrenal ctx ↑ aldosterone (↑↑↑ in hyponatremia, hyperkalemia)kidney antidiuretic, antinatriuretic

↓ glomerular filtrationCV direct vasoconstrictor on VSMCs ↑BP

↑ inotropy w/ little change in HR (via baroreceptor)peripheral ANS

sympathetic: ↑NE, ↑ sensitivity of tissues adrenal medulla catecholamine release

CNS central pressor response ↑ADH, ACTH thirst and sodium appetite

Effects of Aldosterone: Na+ retention K+/Mg++ loss baroreceptor dysfxn impaired arterial compliance prevention of myocardial NE uptake

regulation of sodium transport in colon, sweat glands, and salivary glands

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ATI sensitive to Losartan VSMC kidney brain adrenal ctx pituitary PLA2, PGs, etc.

AT2 (inducible) uterus brain highest in fetus

Week 3T Lipoproteins and Cholesterol I. BackgroundII. TriG and phospholipids are same except phosplipids have PO4 instead of 3rd

FAIII. Lipoproteins

a. size = ↓density b. Most important = B100c. Triglyceride rich

i. LDL from intestines to tissue (exogenous); VLDL from liver to tissue (endogenous)IV. ApoBcontaining (atherogenic) lipoproteins

a. Exogenous pathway of lipoprotein metabolism i. Chylomicrons go into lymph in gut

ii. ApoB-48, C-II on surface, packaged in enterocytesiii. ApoC-II required for interaction with LPL on surface of endothelium iv. Happens in adipose, liver, and skeletal muscle

b. Endogenous pathwayi. Release TriGs from adipose liver

ii. Packaged in VLDLs tissue iii. ApoB100 and C-IIiv. Majority of lipids in the system (from

endogenous)v. Becomes IDL LDL (majority)

V. Classification (Frederickson/Levy) a. Based on what’s elevated

VI. Hyperlipoproteinemia a. 1ary conditions

i. Familial chylomironemia Syndromes (FCS, type I)1. Deficiency in LPL, can’t hydrolyze chylomicrons 2. Deficiency in Apo C-II, phenocopies the first 3. Sx: eruptive xanthomas4. Complications: PANCREATITIS

ii. Familial dysbetalipoproteinemia (FD, Type III)1. Mutation in ApoE, can’t bind to receptor, ↓uptake of chylomicrons, ↓uptake of IDL2. ApoE4 (alzheimers) 3. ApoE2 (FD),but not 100% penetrant , CV disease4. Sx: Tuberos xanthomas, palmar xanthomas

iii. Familial hypercholesterolemia (FH, Type IIa)1. Mutation in LDL-R in liver2. LDL, early atherosclerotic disease 3. Heterozygous corneal arcus, xanthelesma, tendon xanthoma @ Achilles tendon (pathognomic)4. Homozygous large, cutaneous xanthomas on hand 5. Defined the causal role of cholesterol in atherosclerotic disease

iv. Familial defective apoB-100 (FDB, Type IIa)1. ApoB is ligand for LDL-R2. Amish population3. No B-100

v. Autosomal dominant hypercholesterolemia (ADH3; Type IIa) 1. PCSK9 gain of function mutations 2. PCSK9 is a secreted protein that targets LDL-R for destruction3. SO GOF mutation causes LDL

vi. Familial hyperTRIG (FHTG, Type IV = VLDL or V = CM+, VLDL ) 1. Some mechanistically unclear block is conversion from

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2. Slightly TriG, VLDL, block in conversion to CE, LDL normal 3. Type V can be precipitated by exacerbation of Type IV by poor diet or ETOH

vii. Familial combined HyperLipidemia (FCHL)1. Most common inherited lipid disorders 2. VLDL and LDL3. Cholesterol and TriGs4. Defect = overproductionof VLDL, in turn LDL5. 1:100/1:2006. Sx: premature coronary disease but NO xanthomas

b. Mostly 2ary i. Diet, EtOH, Ins-R/T2D, hypoThyroidism, Nephrotic syndrome, CRF, meds

ii. T2d: VLDL overproduction due to Insulin resistant state VII. Coronary Disease and Lipoproteins

a. Apo(a) Lp(a) i. Homoglogous to plasminogen

ii. Function unknowniii. Genetically determined,iv. level of Apo(a) = risk

b. LDL and ↓HDL are independent risk factor for HD

c. HDL i. Lipoproteins A-I and A-II

ii. No ApoB iii. AI and AII lipoproteins on surface of HDL iv. Liver makes AI and AII; intestines just AIv. Acts in reverse cholesterol transport

vi. 2ndary causes of ↓HDL 1. Very ↓Fat diet 2. Sedentary, obsesity, T2D, insulin R/T2D

vii. 1ary causes of ↓HDL Hypoalphalipoproteinemia 1. ApoA-I mutation

a. Major structural protein of HDL b. apoA-I Milano HDL<20

i. Not harmful, maybe protective?

2. LCAT mutation a. Tangier’s b. ABCA-1 mutation, can’t eliminate b/c ABCA-1 is a transporter of HDL from cells

outward c. No consequence clinicallsy

3. LCAT mutation a. Normally allows HDL to mature (Free cholesterol builds up)b. Can’t make cholesterol esters

(no estification) c. CV risk d. Cloudy cornea

Week 3U Cholesterol, Pharmacology, and Management I. Management

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a. All adults >20 should get cholesterol panel b. 1ary target = ↓LDL c. 2ary target = ↓TriG, ↓nonHDL Chol, and HDLd. Target LDL

i. CHD/CHD-risk eq <100 (<70) ii. 2+ risk factors <130 (<100)

iii. 0/1 risk factors <160e. TriG (target goals not as clear); BUT >500 pancreatitis f. ↓non-HDL- chol TARGET = LDL-C level + 30mg/dL g. HDL (>40mg/dl)

II. CHOLESTEROL metabolism a. Diet and Liver (more from liver) b. Synthesized from acetyl-CoA and acetoacetyl-CoA c. Rate limiting HMGcoA reductase d. All CHOL ↓ drugs are inhibitors of HMGcoA reductase and mimic structure of HMGCoA

III. Cholesterol regulates gene expression a. Feedback inhibition b. CHOL = ↓cholesterol synthesis (where CHOL works)c. CHOL = ↓LDL-R

IV. Pharmacologic Management of CHOL a. LIFESTYLE 1st b. STATINs

i. block HMGcoA reductase but liver compensates.ii. Net result = synthesis but also LDL-R

iii. RULE OF 6% 1. Starting dose = bang for the buck 2. Titrate: each time 2x [drug] = 6% reduction3. 22% reduction in CV risk/(40mg/dl )lower LDL

iv. Adverse efx1. transaminases 2. Muscle-related (3-5% pts)

a. Myalgia (achy no CK)b. Myopathy (CK)c. Rhabdomyolysis

c. Chol Absorption inhibitors (CAI)i. Prevent reabsorption of luminal absorption

ii. Exetimibe 1. Target NPC1L1 transporter 2. Used with statins

iii. Plant stanols Fibers d. Bile acid sequestrants (BAS)

i. Large molecular weight insoluble compounds ii. Side chains bind bile acids

iii. ↓LDL by 15-25%iv. Can be used as a monotherpay v. Very safe

vi. Efx: GI, can TG

V. Non-medical Tx modalities a. LDL apheresis

VI. TriG axis a. Fibric acid derivatives

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i. Target PPARa in liver ii. ↓TriG

iii. Indications: TG> 500, adjunct to statin in pts w/ persistently TriGiv. SIDEEFX: liver transminases

b. Niacin (Nicotinic acid)i. High does lowers CHOL

ii. Best drug to HDL iii. ↓FFA release in adipocytes through GPR109Aiv. Side EFX: flushing

c. EPA and DHA (Fish oils) i. ↓TG by 30-50%

ii. At low dose can ↓CV riskd. Up and COMING

i. PCSK9 inhibitors to LDLRii. apoB and MTP targets to reduce LDL production

iii. CETP inhibitors (HDL but HDL may be stuck)iv. Liver-specific thyromimetic

Week 3W Management of CHF Systolic Function

↓mortality SEsΒ-blockers YES ↓HRACE/ARB YES K, Creatinine, angioedema, Lasix (diuretic) NO hypovolemia,↓K, Na, renal failure DIG NO Arrythmias, Hydralazine, nitrates YES LUPUS-like syndrome, ↓BPCCBs (amlodipine) NO mortality ↓HR, BPDihydropyridine NO Fluid retention Aldactone YES Gynecomastia,

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