Flashcards in Exam 2 - CV Deck (94):
1
Define dromotropism
- Ability to alter rate of electrical conduction. In heart, this is accomplished at the AV node.
2
Draw and describe AP of a cardiac myocyte
0. Phase 0 (depolarization): fast opening of Na channels – Na influx = depolarization of membrane
1. Phase 1 (early repolarization): Na channels close – some K channels open = K efflux = slight repolarization and beginning plateau phase
2. Phase 2 (plateau): slow opening of Ca channels (L-type, long-lasting) with K channels open = Ca influx countered by K efflux.
3. Phase 3 (rapid repolarization): Ca channels close, K channels open more = K rapidly effluxes causing return towards RMP
4. Phase 4 (RMP): K channels open = inward/outward K flow are equal
see picture
3
Draw and describe the AP of a nodal cell of the cardiac conducting system
4. Phase 4: slow influx of Na through funny Na channel = slow depolarization towards threshold. Note: T-type Ca channel opens briefly = Ca influx briefy providing final depolarization boost to the pacemaker potential.
0. Phase 0: threshold met = slow Ca channels (L-type) open = Ca influx
3. Phase 3: Ca channels inactivated – K channels open = K efflux = repolarization. These gradually close as phase 4 (slow depolarization) is approached.
* note: no phase 1 and 2
see picture
4
Describe the states of the cardiac Na channel
- 1. Resting: activation gate close and inactivation gate open.
- Depolarization occurs and 2. Rapid opening of activation gate occurs = Na influx.
- 3. Inactivation gates close and Na channels enter inactivated / closed state.
- With repolarization, the activation gate closes and inactivation gate opens.
5
What is the role of late Na current in cardiac function? Describe physiology. Clinical relevance.
- Na current peaks at onset of AP and importantly continues throughout systole with what is called a late component (I(sub)Na), partly responsible for maintaining the plateau of the AP in the myocytes (see AP in cardiac myocytes).
- This channel may be responsible for some pathologies in cardiac system and other NM disorders.
a. When enhanced: there is increased intracellular Na causing activation of Na/Ca exchanger = Na exit with Ca entry = intracellular Ca = overload of Ca = electrical instability, after depolarizations, arrhythmias, mechanical dysfunction (abnormal contraction/relaxation). Also seen in NM disorders (seizures, neuropathic pain, myotonia, paralysis)
* If you can block these channels, you can prevent the pathologies from occurring.
6
Describe the difference(s) between nodal tissue depolarization and myocyte depolarization. Why do we care?
- Phase 0 in nodal cells is d/t Ca influx
- Phase 0 in myocytes is d/t Na influx
- Depending on where arrhythmias arise from, pharmacologic tx changes.
7
What is ERP/APD ratio? Why do I care?
- ERP: effective refractory period = duration of AP during which cell is not responsive to additional stimulus
- APD: AP duration = entire duration of AP
- Lower ratio = easier for tissue to be depolarized by abnormal impulses. Antiarrhythmic agent should prolong refractoriness relative to effect on AP duration, ie. increase ratio.
8
Which muscarinic receptors are found in the heart and what is the effect of activating them?
- M2 receptors
1. SA node: decrease HR (-ve chronotropy)
2. AV node: decrease conduction velocity
3. Atrial muscle: decrease atrial contraction
4. Ventricular muscle: decrease ventricular contraction (weak effect)
9
Beta 1 receptor. Location and response when activated?
- SA node: increase HR (chronotropy)
- AV node: increase conduction velocity (dromotropy)
- A and V muscle: increase FOC, conduction, CO and o2 consumption
- His: increase automaticity and conduction velocity
- Kidney: increase renin release
10
Beta 2 receptor. Location and response when activated?
- Blood vessels (all): vasodilation
- Uterus: relaxation
- Ciliary muscle: relaxation, flattening of lens
- Bronchioles: dilation
- SkM: increase glycogenolysis, increase contractility
- Liver: increase glycogenolysis
- Pancreas: increase insulin secretion
11
Alpha 1 receptor. Location and response when activated?
- Radial (dilator) muscle of eye: contraction (mydriasis)
- Arterioles (skin and viscera): contraction
- Veins: contraction (increase venous return and pre-load)
- Bladder trigone/sphincter: contraction
- Vas deferens: ejaculation
- Liver: increase glycogenolysis
- Kidney: decrease renin
12
Receptors responsible for the main source of arteriole resistance?
- alpha-1. Increases TPR, DBP and afterload
13
Alpha 2 receptor. Location and response when activated?
- Prejunctional nerve terminal: decrease NT release and NE synthesis
- Platelets: aggregation
- Pancreas: decrease insulin secretion
14
Mechanisms of arrhythmias
1. Disorders of impulse formation
a. No change in original pace-maker: eg. sinus tach
b. Change in original pace-maker site: ectopic foci, a tach and a fib
c. Triggered activities: refers to abnml upstrokes after initial normal or “triggering” upstrokes
i. EADs (early after-depolarizations): marked prolongation of the cardiac AP (d/t slow heart rate, hypokalemia, drugs) leads to early after-depolarization, which can lead to an abnormal rhythm (eg. TdP)
ii. DADs (delayed after-depolarizations): conditions of SR Ca2+ overload (MI, adrenergic stress, digitalis intoxication, heart failure) may cause a nml AP to be followed by DAD. If it reaches threshold, a secondary triggered beat(s) may occur.
2. Disorders of impulse conduction
a. AV-nodal blocks
b. Re-entry: existence of conduction routes with different conduction velocity (functional d/t MI, drugs, electrolytes OR organic d/t congenital abnormality or scarring)
i. AV nodal re-entrant tachycardia (AVNRT): requires two conduction pathways present in the heart – one slow and one fast. Slow pathway has short refractory period. Fast refractory period with long refractory period. If an atrial premature beat originates and takes the slow pathway and loops back around into the fast pathway (ie. when not in refractory period), then a fast loop circuit is created.
ii. Examples of re-entry arrhythmias = aflutter (every x atrial beats, one goes down to v), AVNRT, accessory-pathway mediated SVT and ventricular re-entry.
15
Types of arrhythmias
- Supraventricular: sinus tach, sinus brady, aflutter, afib, PAT/PSVT, AV nodal tach
- Ventricular: v tach, v fib
16
What is an AVNRT?
- Disorder of impulse conduction in heart. Stands for AV nodal re-entrant tachycardia.
- Requires two conduction pathways present in the heart – one slow and one fast. Slow pathway has short refractory period. Fast refractory period with long refractory period. If an atrial premature beat originates and takes the slow pathway and loops back around into the fast pathway (ie. when not in refractory period), then a fast loop circuit is created.
17
Compare and contrast EAD vs DAD.
- These refer to mechanisms for arrhythmia generation
i. EADs (early after-depolarizations): marked prolongation of the cardiac AP (d/t slow heart rate, hypokalemia, drugs) leads to early after-depolarization, which can lead to an abnormal rhythm (eg. TdP)
ii. DADs (delayed after-depolarizations): conditions of SR Ca2+ overload (MI, adrenergic stress, digitalis intoxication, heart failure) may cause a nml AP to be followed by DAD. If it reaches threshold, a secondary triggered beat(s) may occur.
18
Consequences of arrhythmias
- Compromise mechanical performance: affect SV, decrease CO
- Pro-arrhythmic/arrhythmogenic: vtach converts to vfib
- Thrombogenesis: thrombi form in heart, follow flow to cause vessel occlusion in periphery. Aflutter and fib are commonly associated with thrombi
19
4 mechanisms to decrease spontaneous activity in the heart
1. Decrease the phase 4 slope
2. Increase threshold for AP
3. Increase maximum diastolic potential: membrane potential is decreased further away from resting
4. Increase AP duration
20
Mechanisms by which drug can increase refractoriness of AP
- Na channel blockers.
- Action-potential prolonging drugs: eg. K channel blocker
21
Classes of antiarrhythmic drugs. General mechanism for class (and subclass if any), drug names and indication.
1. Class I:
- MOA: block fast inward Na channels in conductive tissues of heart, therefore decrease max depolarization rate, reduce automaticity, delays conduction, increases ERP/APD.
- Indication: Digitalis or MI-induced arrhythmias
a. 1a: quinidine, procainamide, disopyramide
- MOA: moderate binding to Na channels (moderate phase 0 depo effect), K channel blockage (delayed phase 3 repo, prolonged QRS and QT), Ca channel blocked at high doses (depresses phase 2 and nodal phase 0)
b. 1b: lidocaine, mexiletine
- MOA: weak binding to Na channels (weak phase 0 depo effect), blocks late Na channel (accelerated phase 3 repolarization = shortened APD and QT)
c. 1c: propafenone, flecainide
- MOA: strongest binding to Na channels (strong effect on phase 0 depo, lengthens QRS and APD, QT unchanged, lengthened PR d/t depressed AV node conduction)
2. Class II: beta-adrenergic antagonists
- MOA: decrease SA node automaticity (phase 4), AV node conduction, ventricular contractility
- Indication: SVT and PSVT, only drug to prevent sudden cardiac death in patients with prior MI
3. Class III: dronedarone, amiodarone, sotalol, ibutilide, dofetilide
- MOA: effects on all cardiac target receptors except for adenosine. Main effect = prolong phase 3 repolarization (increase QT)
- Indication: useful for ventricular re-entry/fib arrhythmia
4. Class IV (aka non-DHP CCBs): verapamil, diltiazem
- MOA: cardiac Ca channel antagonists, similar to class II with primary effects on nodal phase 0 depo. It depresses SA node automaticity, AV node conduction and ventricular contractility
22
Quinidine. Class, MOA, indications, adverse effects
- Class Ia antiarrhythmic
- MOA: block rapid inward Na channel, so decreases vmax of phase 0, slows conduction, effects greatest with fast HR. Dose-dependent actions: blocks K (increase APD), blocks alpha (decrease BP), blocks M (increase HR in intact subjects)
- Indications: patients that are refractory to: convert symptomatic afib or flutter, prevent recurrences of afib or flutter, treat life-threatening documental ventricular arrhythmias
- Adverse effects: DIARRHEA, nausea, vomiting, CINCHONISM (tinnitus, hearing loss, blurred vision), HOTN, PROARRHYTHMIC (TDP: K blocked prolongs AP = increased probability for EADs)
23
Procainamide. Class, MOA, indications, adverse effects, other notes
- Class Ia antiarrhythmic
- MOA: blocks rapid inward Na channel, so slows conduction, automaticity, excitability. Blocks K channels to increase APD and refractoriness.
- Indications: acute tx of re-entrant SVT, afib, aflutter associated with WPW (pre-excitation syndrome) and treat documented life-threatening ventricular arrhythmias (IV loading takes 20 mins though)
- Adverse effects: arrhythmia aggravation; contraindicated in long QT syndrome, history of TDP and hypokalemia); heart block and sinus node dysfunction. Can cause SLE-like syndrome (arthralgia, fever, weakness, pericarditis, skin lesions, anemia, etc.), GI nausea and vomiting very common, decreased kidney functions
- Other: little vagolytic activity compared to quinidine.
24
Lidocaine. Class, MOA, indications, adverse effects, other notes
- Class 1b antiarrhythmic
- MOA: blocks open and inactivated Na channels, reducing Vmax – this leads to shortened cardiac AP (effect in ischemic tissue). Lowers slope of phase 4 altering threshold for excitability. If abnormal conduction system exists, effect variable (slow ventricular rate, potentiates infranodal block)
- Indications: Second choice behind amiodarone for life-threatening or symptomatic arrhythmias
- Adverse effects: tinnitus, seizure with rapid bolus. High dose = CNS effects. Be careful in use in HF patient where decreased clearance and high concentrations can build up.
- Other: has extensive first-pass metabolism (requires IV use), need multiple loading doses and Md infusion
25
Propafenone. Class, MOA, indications, other notes
- Class Ic antiarrhythmic
- MOA: strong inhibitor of Na channel, can inhibit beta-adrenergic receptors as structurally similar to propranolol
- Indications: atrial arrhythmias, PSVT and ventricular arrhythmias –
- Other notes: NB in patients with no or minimal heart dz and preserved ventricular function as it has a severe effect on LV function and also decreases HR.
26
Flecainide. Class, MOA, indications, other notes
- Class Ic antiarrhythmic
- MOA: potent Na channel blockade, which prolongs phase 0 and widens QRS. It markedly slows intraventricular conduction.
- Indications: only for refractory life-threatening ectopic ventricular arrhythmia
- Other notes: not first line agent d/t propensity for fatal pro-arrhythmic effects
27
Beta adrenoceptor antagonists. Type and names.
1.) 1st generation: non-selective: b1 = b2: propranolol, nadolol, timolol, pindolol.
2.) 2nd generation: selective: b1 >>> b2: AMEBA mnemonic = atenolol, metoprolol, esmolol, betaxolol, acebutolol
3.) 3rd generation (mixed alpha-beta antagonists): vasodilatory: b1=b2 >= a1>a2: labetalol, carvedilol
28
Beta-receptor antagonist effect in heart
- Decrease ventricular FOC/contractility, decrease SA node automaticity (phase 4), decrease AV node conduction
29
What anti-arrhythmic purpose are beta-blockers indicated for?
- supraventricular arrhythmias d/t excessive SNS activity
- ONLY antiarrhythmic drug clearly effective in preventing sudden cardiac death in patients with prior MI
30
Amiodarone. Class, MOA, indications, other notes, adverse effects
- Class III
- MOA: block K channels (prolongs refractoriness and APD), blocks NA channels in inactivated state, blocks Ca channels (slows SA node phase 4), slows conduction through AV nodes, non-competitive blockage of alpha-, beta- and M receptors
- Indications: wide range of arrhythmias: converts and slows aflutter, AVRT, tachycardia associated with WPW, PO use in life-threatening VT of VF, IV for acute termination of VT or VF replacing lido as first-line in out-of-hospital cardiac arrest (when one cannot determine what the arrhythmia is)
- Other: metabolized to DEA, which has anti-arrhythmic potency >= amio. Has large VD (rapidly concentrates in tissue). All tissues must be saturated, otherwise it rapidly redistributes out of myocardium, which may be responsible for early recurrence of arrhythmias after discontinuation or dose reduction. Long half-life.
- Adverse effects: large dose causes decrease in cardiac contractility and peripheral resistance = hypotension. Most serious = lethal interstial pneumonitis (frequent in those with pre-existing lung dz, can be reversed, but must to CXR regularly). Also hyper/hypo-thyroidism. Others: corneal microdeposits, photosensitivity and elevated serum hepatic ez levels.
31
CCBs. Classes, drug names, MOA/effects, indications
1. Classes and drug names
a. dihydropyridine (DHP): -dipine (nifedipine and others) – effect mostly in vasculature
b. non-dihydropyridine (NDHP): verapamil and diltiazem – effect mainly in heart
2. Effects:
- Vascular SM cells (DHP mostly 10:1): markedly in arteries and arterioles than veins. Note: little to no effect on other SM, no effect on SkM
- Cardiac myocytes (NDHP mostly): negative inotropic effect
- SA and AV nodal cells (NDHP only): negative chronotropic and dromotropic effects
3. Indications: systemic HTN, angina pectoris, SVT, post-infarct protection (non-DHP)
32
Verapamil. Class, MOA, indications, adverse effects, other notes
- Non-DHP Calcium channel blocker (CCB)
- MOA: Blocks mainly L-type (slow) Ca channels in nodal tissue to decrease SA automaticity (decrease HR), decrease AV conduction (increase PR) and decrease ventricular contractility. Favorable in Reynaud syndrome, migraine HA, arrhythmias and high-normal or tachy HR.
- Indications: SVT (IV convert, PO maintain), rate control in afib, angina pectoris, HTN (first-line or add-on)
- Other: ineffective on ventricular arrhythmia (no effect on ventricular Na conduction). Alternative to beta-blockers in CAD.
- Adverse effects: constipation, exacerbate CHF, HA, flushing, dizziness, ankle edema, hypotension, AV heart block when used with beta-blockers. Contraindication: WPW syndrome with afib, vtach, sick sinus syndrome, pre-existing AV node dz. Avoid in second or third degree heart block and for LV dysfunction. Unfavorable in peripheral edema and low-nml HR patients.
33
Adenosine. Class, MOA, indications, adverse effects, other notes
- Miscellaneous anti-arrhythmic
- MOA: Activates A1 receptor in SA and AV nodes leads to activation of K+ sensitive leads to SA node hyperpolarization and decrease firing rate, shorten of AP duration of atrial cells, depression of AV conduction velocity. Activates A2 receptor in vasculature leads to activation of K+ sensitive leads to vasodilation. Stimulates pulmonary stretch receptors.
- Indications: PSVT = #1
- Adverse effects: hypotension, flushing, complete heart block, CNS effects, dyspnea
- Other: must use IV bolus to a central vein as half-life is 10-15 sec
34
Drugs to treat bradycardia
- Atropine (vagal block to increase HR), isoproterenol (beta-1 stimulation to increase HR)
35
Classes of diuretics, drugs and sites/mechanism of action
1. Carbonic anhydrase (CA) inhibitors (CAIs)
- Drug names: acetazolamide, dichlorphenamide, methazolamide
- MOA: PCT; Na/H exchanger and carbonic anhydrase – decrease bicarb reabsorption
2. Osmotic agents
- Drug names: mannitol, glycerin, urea, isosorbide
- MOA: increase osmotic pressure in tubular fluid
3. Loop diuretics (aka NKCC inhibitors)
- Drug names: furosemide (Lasix), bumetamide, ethacrynic acid
- MOA: Thick ascending limb of Henle; Na/K/Cl (NKCC) inhibitors preventing reabsorption of solute, increases fractional Ca and Mg excretion via decrease in lumen-positive potential, also causes venodilation
4. Thiazides
- Drug names: chlorthalidone, HCTZ, metolazone, indapamide
- MOA: DCT; NCC
5. Renal-epithelial Na channels
- Drug names: amiloride, triamterene
- MOA: blocks epithelial Na channels on principal cells in late DCT and initial collecting ducts = natriuresis and preventing of K loss
6. Aldosterone-receptor antagonists
- Drug names: spironolactone, eplerenone
- MOA: block aldosterone Rs in collecting tubules leading to decrease in Na reabsorption = natriuresis. Decrease loss of K.
7. ADH antagonists
- MOA: medullary collecting duct; vasopressin antagonist
36
Acetazolamide. Class, MOA, indications, adverse effects, other notes
- CAI diuretic
- MOA: decrease bicarb reabsorption (ie. increase excretion) at PCT = increase solute delivery to macula = TGF mechanism = increase afferent arteriolar resistance = decrease RBF and GFR. Increased bicarb excretion = increase NaCl excretion = diuresis & K excretion. Also decrease bicarb formation and inhibition of titratable acid and NH4+ secretion = increase urine pH and metabolic acidosis promoting.
- Indications: glaucoma, acute mountain sickness, induce urinary alkalinization, edema (when combined with NKCC and NCC inhibitors) – use these to cause metabolic acidosis primarily.
- Adverse effects: hyperchloremic metabolic acidosis, renal stones, renal loss of K
- Contraindications: cirrhosis (drug leads to increase plasma NH4+)
37
Mannitol. Class, MOA, indications, adverse effects, other notes
- Osmotic diuretic
- MOA: agent is freely filtered in glomerulus, but poorly absorbed. In tubular fluid, osmotic pressure is increased = decrease free fluid absorption. Also distally it stimulates K secretion d/t increased flow.
- Indications: prophylaxis of acute renal failure, cerebral edema, dialysis disequilibrium syndrome, acute attacks of glaucoma
- Adverse effects: ECV expansion (pulmonary edema in patients with heart failure, hyponatremia or hypernatremia depending on speed of loss of electrolytes)
- Contraindications: anuria d/t renal dz, impaired liver function (with urea drug), active cranial bleeding (mannitol and urea)
38
Furosemide (Lasix). Class, MOA, indications, adverse effects, other notes
- NKCC inhibitor (loop diuretic)
- MOA: inhibits Na/K/2Cl co-transporter (NKCC) = inhibition of solute reabsorption from the TAL segment in kidney. Increases fractional Ca and Mg excretion by decreasing the lumen-positive transepithelial potential that normally promotes reabsorption. Also venodilation.
- Indications: pulmonary edema, CHF, acute renal failure, hypercalcemia (w/saline)
- Adverse effects: hypokalemia!, hyponatremia, hypocalcemia, hypomagnesia, ototoxicity, hyperuricemia
39
Chlorthalidone, HCTZ. Class, MOA, indications, adverse effects
- Thiazide class, NCC inhibitor diuretic
- MOA: inhibit the Na/Cl transporter (NCC) in the DCT = decrease Ca excretion = vasorelaxation
- Indications: HTN (less effective if reduced renal function) that is uncomplicated (first-line or LV dysfunction and previous ischemic stroke), edema (CHF), hypercalciuria (stones) and nephrolithiasis, nephrogenic diabetes insipidus. Favorable in those with osteoporosis (or risk) and high-nml K.
- Adverse effects: avoid in those with sulfa drug allergies, gout, hyponatremia, hypokalemia. Unfavorable for those with gout, pre-DM, low-nml K, elevated BGL.
40
Amiloride. Class, MOA, indications
- Renal epithelial Na channel blocker
- MOA: blocks epithelial Na channels on principal cells in late DCT and initial collecting ducts = natriuresis and preventing of K loss
- Indications: K-sparing in hypokalemic alkalosis, use with loop diuretics or thiazides to prevent hypokalemia
41
Spironolactone. Class, MOA, indications, adverse effects, other notes
- Aldosterone-receptor antagonist
- MOA: block aldosterone Rs in collecting tubules leading to decrease in Na reabsorption = natriuresis. Decrease loss of K.
- Indications: edema, HTN (w/ thiazide of loop): add-on for resistant HTN & CAD, LV dysfunction, standard therapy of heart failure, primary hyperaldosteronism, refractory edema t/d secondary aldosteronism. NB: prevent LV remodeling and cardiac fibrosis, prevention of sudden cardiac death, hemodynamic effects, vascular effects. Favorable in low-nml K and CKD.
- Adverse effects: hyperkalemia, metabolic acidosis in cirrhotic patient (can affect proton pump), other steroid binding effects: gynecomastia, impotence, hirsutism etc. Unfavorable in high-nml K.
42
Main mechanisms behind diuretic therapy
- TPR decrease, Loss of Na
43
Anti-hypertensive classes of drugs, MOA and drug names
1. ACE inhibitors (-opril)
- MOA: ACE blocker in RAAS system
- Drugs: captopril, lisinopril, fosinopril
2. Angiotensin receptor blockers (ARBs) (-sartan)
- MOA: angiotensin 1 receptor blocker
- Drugs: losartan, valsartan, candesartan
3. Calcium channel blockers (CCBs)
- MOA: calcium channel inhibitor
a. DHP group (-dipine): nifedipine, amlodipine, felodipine
b. Non-DHP group: verapamil, diltiazem
4. Diuretics and aldosterone antagonists
a. Thiazides: chlorthalidone, HCTZ
b. Aldosterone antagonists: spironolactone, eplerenone
5. Beta adrenergic blockers
- MOA: beta-receptor antagonists
- Drugs: propranolol, metoprolol, pindolol, labetalol
6. Other:
a. alpha blockers: prazosin, doxazosin, terazosin
b. arterial vasodilators: hydralazine, minoxidil, sodium nitroprusside
c. central alpha-2 agonists: clonidine, alpha-methyldopa
d. direct renin inhibitor: aliskiren
e. rauwolfia alkaloids: reserpine
44
Define HTN
- Per AHA: > 140/90
45
Define hypertensive crisis vs emergency vs urgency
- HTN crisis: includes both urgency and emergency
- Urgency: SBP >=180 or a DBP >= 120 with no associated acute end organ (CNS, kidney, brain, retina) damage. Requires reduction over hours to days.
- Emergency: markedly elevated BP w/presence of acute end organ damage. Requires reduction within minutes to hours.
46
Define resistant HTN
- BP uncontrolled despite optimal use of 3 or more anti-hypertensive drugs of which one is diuretic
47
What is pseudo-resistant HTN?
- Uncontrolled BP attributed to white coat effect, poor adherence to meds or incorrect BP measurement techniques.
48
Risks for resistant HTN?
- Older age, obesity, CKD, DM, obstructive sleep apnea, consumption of high salt diet, AA, female
49
Etiology of HTN
1. Primary: idiopathic (essential), genetic, lifestyle
2. Secondary: common (renal parenchymal dz, obstructive sleep apnea, renal artery stenosis, primary aldosteronism) and uncommon (pheochromo, cushing, hyperparathyroidism, coarctation of aorta)
50
Intent for treating HTN
- reduce risk of CV events and thereby reduce CV morbidity and mortality
51
Non-pharmacological approach to treat HTN
- DASH: dietary approach to stop HTN
- reduce weight (biggest factor)
- lower intake of sodium
- physical activity
- moderation of etoh consumption
52
Why is it that people with HTN don’t have reflex brady?
- Baroreflex (Na/water changes in kidney, SNS) resets such that the increased pressure becomes a normal consideration for the system.
53
First-line tx in HTN pt DM patient
- ACEi or ARB
54
First-line tx in HTN pt with CKD
- ACEi or ARB
55
First-line tx in HTN pt with CAD
- beta-blocker and ACEi or ARB
56
First-line tx in HTN pt with LV dysfunction
- Diuretic, ACEi or ARB, and beta-blocker
57
First-line tx in HTN pt with previous ischemic stroke
- ACEi with or without thiazide diuretic
58
Describe RAAS
- Low renal perfusion, increase catecholamines = renin release = angiotensinogen to ang I – ang I converted to ang II by ACE = ang II = aldosterone release + vasoconstriction – increase Na retention and H2o = increase BP and increase renal K excretion
59
Effect of angiotensin II
- increase aldosterone synthesis and secretion
- increase vasoconstriction
- increase release of vasopressin
- increase release of adrenal catecholamines
- increase central SNS outflow
60
Captopril, lisinopril, fosinopril. Class, MOA, indication, adverse effects, other
- Class: ACE-inhibitor
- MOA: a.) block ACE preventing conversion of ang I to ang II and b.) block ACE preventing bradykinin degradation
- Indication: HTN first-line (or add-on), compelling indications for DM, CKD, CAD, LV dysfunction, previous ischemic stroke, favorable in low K patient, pre-DM and albuminuria patient.
- Adverse effects: contraindicated in pregnancy, bilateral renal stenosis, hx of angioedema. Potential unfavorable in hyperkalemia, volume depletion. Hypotension, coughing, angioedema, increase plasma K, acute renal failure, fetopathic potential, skin rash
- Other: cleared by kidney (reduce dose in kidney failure patient), elevated renin causes hyperresponsiveness to ACEi (reduce dose in high renin plasma pts, ie. those with heart failure and Na-depleted). Good responders (young/middle-age Caucasians), poor responders (elderly AA)
61
Losartan, valsartan, candestan. Class, MOA, indication, adverse effects, other
- Class: ARB (angiotensin receptor 1 blocker)
- MOA: blocks ang receptor 1 blocker = vasodilation, decrease ADH release, decrease aldosterone secretion, decrease release of adrenal catecholamines, inhibition of noradrenergic neurotransmission, decrease SNS tone, renal function changes
- Indication: HTN first-line (or add-on), compelling indications for DM, CKD, CAD, LV dysfunction. Commonly alternative to ACEi. Favorable in low K patient, pre-DM and albuminuria patient.
- Adverse effects: contraindicated in pregnancy, bilateral renal stenosis. Potential unfavorable in hyperkalemia, volume depletion.
62
Nifedipine. Class, MOA, indication, adverse effects
- Class: DHP CCB
- MOA: relaxation of vascular SM cells (10:1 compared to non-DHP): markedly in arteries and arterioles than veins. Note: little to no effect on other SM, no effect on SkM.
- Indication: HTN first-line or add-on for uncomplicated HTN. Add on for DM and CAD. Favorable in Reynaud syndrome, elderly with isolated systolic HTN, cyclosporine-induced HTN.
- Adverse effects: avoid in LV dysfunction. Unfavorable in peripheral edema and in those with high-nml HR or tachy.
63
T/F. Nifedipine can be used in LV dysfunction.
- False. Avoid use in LV dysfunction as these increase LV work (I think).
64
What beta-blockers are recommended for HTN? MOA, physiologic effects? Adverse effects? Contraindications?
- General effects: decrease FOC, decrease HR = decrease BP in HTN patients. No effects on normotensive individual. Decrease myocardial o2 consumption. Decrease renin release.
- Indication: first line for CAD, LV dysfunction, add-on for uncomplicated HTN and DM. Favorable for migraine HA, tachyarrhythmia, high nml HR or tachyarrhythmia, hyperthyroidism, essential tremor, preop HTN.
- Adverse effects: bronchoconstrictor, Fatigue, Worsening peripheral vasculature dz (beta-2 blocking), Decreases sexual functions, Increased incidence of DM, Masking symptoms of hypoglycemia (NB!!!) – hypoglycemia symptoms = HR, palpitations via neural control of SNS. Now with agonists, HR and palpitations not present. Sweating still remains
- Propranolol (non-selective: beta-1 = beta-2 antagonist)
- Metoprolol (cardio-selective)
- Pindolol (ISA): In addition to inhibiting the receptors (beta-blockers), they also stimulate the receptors.
- Labetalol (mixed alpha/beta)
65
Non-CV event risk-reducing anti-HTN drugs
- Alpha-adrenergic receptor blockers, arterial vasodilators, central alpha-2 agonists, direct renin inhibitors, Rauwolfia alkaloids
66
What alpha-1 adrenergic receptor blockers are used in HTN? MOA? Adverse effects?
- Drugs: prazosin, doxazosin, terazosin
- MOA: (a1 >>> a2) antagonist = relaxes arterial, venous and prostate SM. Lower BP, reflex tachy.
- Indication: HTN, BPH, also lowers LDL/TG and TC
- Orthostatic HoTN with mild tachy esp with first dose, sexual dysfunction
67
What central alpha-2 agonists are used in HTN? MOA? Adverse effects?
- Drug = clonidine (catapres) and alpha-methyldopa
- MOA: alpha-2 central agonist = decrease central SNS outflow = decrease BP
- Indication: Systemic HTN (clonidine and alpha-methyldopa)
a. Clonidine: there is transdermal that is useful for labile HTN, hospitalized pt who cannot take meds PO and pts who are prone to early morning BP surges
b. Alpha-methyldopa: exclusively in gestational HTN and in chronic HTN in pregnancy
- Adverse effects: Xerostomia, sedation, HoTN, rebound HTN if stopped abruptly, hepatotoxicity (alpha-methyldopa), direct coombs test pos (alpha-methyldopa)
- Note: clonidine optimally used with diuretic to diminish fluid retention
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Hydralazine. Class, MOA, indications, adverse effects
- Class: arterial vasodilator, anti-HTN
- MOA: decrease IP3 induced Ca release = decrease contraction; open Ca activated K channels in SM = relaxation; effect on arterioles, minimal to no on veins
- Indications: add-on to resistant HTN esp. safe in those with severe CKD and in pregnant women (gestational HTN)
- Adverse effects: drug-induced lupus, compensatory tachy and Na retention (used in combination with diuretic and beta-blocker or NDHP CCB to mitigate these effects).
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Minoxidil. Class, MOA, indications, adverse effects
- Class: arterial vasodilator, anti-HTN
- MOA: activates ATP-dependent K channels = relaxation of arteriolar VSMCs, no effect on veins. CV effects = decrease BP, increase blood flow to heart, skin (Rogaine), skeletal muscle, GI tract, CNS; increase CO, increase renal blood flow.
- Indications: severe, refractory HTN; use in combo with beta-blockers and diuretics
- Adverse effects: fluid and salt retention, reflex increase in myocardial contractility, hypertrichosis
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Sodium nitroprusside. Class, MOA, indications, adverse effects
- Class: arterial vasodilator, anti-HTN
- MOA: donates NO leading to cGMP mediated Ca sequestration = potent vasodilator (rapid onset and short duration 1-10 mins), decrease afterload and preload (venous effect too!)
- Indications: HTN emergency (IV), rapid mgmt. of CHF
- Adverse effects: methemoglobineia, cyanide poisoning (CN in formulation), cell death d/t inhibition of cellular respiration
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Aliskiren. Class, MOA, indications, adverse effects
- Class: direct renin inhibitor
- MOA: binds to catalytic site of renin: prevents angiotensinogen cleavage to ang I
- Indication: mono or combo (with ACEi, thiazide, ARB or CCB) therapy for HTN
- Adverse effects: hyperkalemia in pts with CKD (esp if combined with K sparing drug), never use in pregnancy
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Rauwolfia alkaloid used in HTN. MOA, adverse effects
- Reserpine
- MOA: block transport of NE into storage granules = reduction of NE from nerve ending = decrease SNS tone, decrease in peripheral vasculature resistance = decrease BP, decrease catecholamines in brain = decrease CO
- Indication: rarely used in HTN d/t perceived adverse effects. Most effect when combined with thiazide diuretic.
- Adverse effects: sedation, depression, decreased CO, orthostatic HoTN, strong sympatholytic effect = increased PSNS activity: nasal congestion, increase gastric acid secretion, diarrhea, brady. Low dose = minimal side effects.
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Preferred diuretic for resistant HTN
- Chlorthalidone
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Other non-pharmacologic, non-lifestyle modalities used to tx resistant HTN
- Selective renal artery sympathetic denervation
- Baroreflex activation therapy: increase baroreceptor firing = decrease SNS drive, increase PSNS tone.
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Anti-HTN meds avoided/contraindicated in pregnancy?
- Avoid: diuretics, atenolol, nitroprusside
- Contraindicated: ACEi, ARBs
- Best = methyldopa, labetalol, hydralazine
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What is the difference between angina (stable angina), unstable angina (rest angina) and acute MI?
- Stable angina: CP/heaviness, radiating to neck/jaw/epigastrium/shoulder/left arm. Precipitated by exercise, cold weather, emotional stress. Lasts 2-10 mins.
- Unstable angina: same as angina, may be more severe. Typically =30 mins often associated with SOB, weakness, nausea and vomiting.
- Acute MI: same as angina, may be more severe. Sudden, lasting >=30 mins often associated with SOB, weakness, nausea and vomiting.
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What causes anginal pain?
- Ischemia d/t release of brady and adenosine onto nociceptive afferents
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Which medications decrease o2 demand in heart that have utility in ischemia? Which increase o2 supply?
- Decrease o2 demand: Beta-adrenergic blockers, Some CCBs, Organic nitrates (nitroglycerin, isosorbide dinitrate, isosorbide mononitrate)
- Increase o2 supply: vasodilators (CCBs), statins, anti-thrombotics
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Nitroglycerin, isosorbide dinitrate, isosorbide mononitrate. Class, MOA, indication, adverse effect, other notes (what is nitrate tolerance)
- Class: organic nitrates
- MOA: prodrugs – denitrification by mitochondrial aldehyde reductase = NO – activates soluble GC = decrease Ca2+ influx = phosphorylates MLCK = vasorelaxation. This leads to decreased ventricular volume and preload. No effect on peripheral vascular resistance. Little to no effect on coronary resistance avoiding coronary steal (reduction in coronary flow)
- Indication: acute angina (incl. prophylactically); CHF, give ISDN+hydralazine in African Americans with CHF (esp d/t systolic dysfunction); unstable angina and acute MI
- Adverse effect: HA (common, early), hypotension (titrate-up ISDN dose over days) – ensure pt supine with first dose, erythema or local edema at site, methemoglobinemia (rare)
- Other notes:
c. Nitrate tolerance: potent effect acutely, but when significant [ ] in 24-hr period = tolerance. ? Mechanism. Clinical relevance? Effects can be maintained when using regimens allowing for nitrate-free or low [ ] for several hours per day.
d. Nitro: half-life in a few minutes, give SL or TD. ISDN: half-life ~40 mins, available in sustained release form (QD dosing) to avoid tolerance, PO or SL. ISMN: no first-pass metabolism, also in sustained release form (QD dosing) to avoid tolerance.
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What is the therapy of choice in acute HF and active ischemia?
- Organic nitrates (nitroglycerin, etc.)
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Drug of choice in African American patient with CHF?
- ISDN and hydralazine combo
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Arterial pressure is a representation/function of afterload or preload? What about ventricular filling?
- Arterial pressure is a function of afterload
- Ventricular filling is a function of preload
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Frank-Starling phenomenon
- Relationship between preload and contractility. Higher preload = more contractility = more SV. Up to a point though.
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Anrep phenomenon
- Relationship b/w afterload and contractility. If you increase afterload, you can increased contractility.
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Bowditch phenomenon
- Relationship b/w HR and contractility. Increase in HR associated with increase in contraction. Pt with tachycardia able to maintain CO.
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Review contractile status/ventricular performance chart
see picture
- If heart is in rest contractile status. To walk from point A to A’, you must increase preload by 1
- If heart is in exercise contractile status. To walk from Bnot to B, you must increase preload by 2
- Thusfar: When in exercise contractile status, you need a smaller increase in preload when compared to rest contractile status.
- In heart failure: to go from rest C to walking C’, require a much larger increase in preload.
- Ultimately we want drug to move patient above curve.
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Describe pathophysiology of heart failure
- As a result of diseased state, cardiac remodeling occurs leading to heart failure, meaning there is elevated cardiac filling pressure and decreased CO.
- As a result, this is accompanied by compensatory neurohormonal responses including activation of SNS, RAAS.
- Ultimately the compensatory response leads to worsened cardiac remodeling, further decrease in cardiac output and elevated cardiac filling pressures. In the end a vicious cycle ensues. Therefore many pharmacologic interventions are required to break the cycle.
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ACC/AHA classification for heart failure. What meds are required at each?
- Stage A (high risk for developing HF): HTN, CAD, DM and family hx of cardiomyopathy. Meds = ACEi or ARB.
- Stage B (asymptomatic HF/pre-HF): previous MI, LV systolic dysfunction, asymptomatic valvular dz. Meds = ACEi or ARB; beta-blocker
- Stage C (symptomatic HF): known structural heart dz, SOB/fatigue, reduced exercise intolerance. Meds = Same as above + diuretic (fluid retention), aldosterone antagonist (symptomatic LVD), hydralazine/nitrates (AA race), digoxin (afib)
- Stage D (refractory end-stage HF): marked sx at rest despite maximal therapy. Meds = same as above + positive inotropes (digitalis)
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Review hemodynamic responses to pharmacologic interventions in heart failure graph
see picture
- NB, want vasodilator + something else. Much farther to left without low output symptoms = better.
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In treating CHF, is it better to increase or decrease ventricular filling pressure? SV?
- Increase SV with decrease in ventricular filling pressure
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Factors that lead to increase in intrinsic myocardial contractility for use in heart failure. What are the pharmacologic interventions to accomplish these?
- Beta-1 receptor agonist activation: isuprel, dobutamine, dopamine, epi, NE.
- Also increase in beta-1 receptor density: beta-1 receptor antagonists (metoprolol and carvedilol) – how?
- Increase in cAMP (via AC): phosphodiesterase inhibitors (amrinone, milrinone)
- Increase ultimately in Ca: cardiac glycosides (digitalis aka digoxin)
- Increase in rate, increase in force, increase in rate of relaxation
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Digoxin (digitalis). Class, MOA, indications, adverse effects, other, antidote
- Class: cardiac glycoside
- MOA: blocks the Na/K atpase leading to buildup of Na intracellularly. This reduces Na/Ca exchanger leading to increase in Ca intracellularly. Contraction increased as a result of enhanced cytoplasmic Ca – rate, force and relaxation rate. This promotes +ve inotropic effect leading to decrease EDV and decrease in ESV = decrease in pulmonary and systemic venous pressure. Reflex SNS decreased = decrease preload, afterload and HR. +ve vagal effect = decrease AV conduction, increased PR interval (lengthened ERP), decreased QT (shorter APD). There is an increase in coronary flow d/t decrease in hypertrophy. Renal resistance decreases = increase RBF/GFR = increase urine output. It is pro-arrhythmic = ST depression (hockey stick).
- Indications: tx of heart failure especially CHF with Afib
- Adverse effects: dig intoxication (therapeutic index
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Characteristic ECG findings with digoxin.
- it is a proarrhythmic causing ST depression (typical hockey stick shape)
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