Module C: 10-13 Flashcards
The majority (~95%) of hypertension is classified as _______ (primary / secondary) hypertension
Primary
this is hypertension that can not be attributed to a specific cause.
normal ranges for SBP are _______ for normal, _________ for prehypertension, _________ for stage 1 hypertension, and _________ for stage 2 hypertension
Normal: <120
Prehypertension: 120-139
Stage 1 HT: 140-159
Stage 2 HT: 160+
The diuretics that are most frequently used in the treatment of hypertension are:
Thiazide diuretics
The 5 common classes of diuretic and their site of action are:
- Thiazide and thiazide-related
- NaCl Symporter in DCT
- Loop
- NaK2Cl costransporter in thick ascending limb of loop of henle
- Potassium sparing
- Aldosterone receptors or Na channels in CD
- Osmotic
- Cause osmotic diuresis
- Carbonic anhydrase inhibitors
- Carbonic anhydrase near PCT
Describe the effects of thiazide diuretics on electrolyte balance
Increased excretion of sodium, potassium, and magnesium. Retention of Calcium
The hypokalemia caused by thiazide and loop diuretics may cause a secondary ___________ (blood pH imbalance)
Hypokalemic metabolic alkalosis
body cells exchange H+ ions for potassium in an attempt to preserve serum potassium
Explain why thiazide diuretics may be used in treatment of nephrolithiasis
thiazides reduce calcium excretion and thereby reduce calcium concentration of the filtrate
Apo-Hydro (Hydrochlorothiazide)
- thiazide diuretic
- Acts on NaCl symporter in DCT, causing natriuresis, kaliuresis, and Calcium retention
- First line diuretic for treatment of hypertension and edematous states.
- Also used in treatment of nephrolithiasis, diabetes insipidus, and renal disorders
- Common side effects: hypokalemia, hyperglycemia, hyperlipidemia, hyperuricemia
_______ diuretics are called “high-ceiling” diuretics because they produce a __________ (dose - dependent / flat) dose-response curve.
loop** diuretics are called “high-ceiling” diuretics because they produce a **dose-dependent dose-response curve.
Describe the effects of loop diuretics on electrolyte balance
Increased excretion of sodium, potassium, magnesium, and calcium
contrast this with the calcium-sparing effects of the thiazide diuretics
Common non-electrolyte side effects of thiazide diuretics include:
Hyperuricemia, hyperglycemia, and hyperlipidemia. May also cause a hypokalemic metabolic alkalosis
result of inhibition of uric acid secretion from the PCT and decreased insulin sensitivity
The preferred diuretics for treatment of edematous states (CHF, pulmonary edema, cirrhosis, nephrotic syndrome, etc.) are:
loop diuretics
especially due to their dose-dependent response across the therapeutic range
Lasix (Furosemide)
- Loop diuretic
- Inhibits the Na/K/2Cl cotransporter in thick ascending limb of loop of henle
- high-ceiling dose-dependent diuretic
- Preferred first line diuretic for edematous states
- Adverse effects: hypokalemia, hypomagnesemia, hypocalcemia, hyperglycemia, hyperuricemia, ototoxicity
_______ is a diuretic that has an anti-androgenic effect and is therefore used in treatment of PCOS
spironolactone
The two classes of potassium-sparing diuretics are:
sodium-channel blockers and aldosterone receptor antagonists
Treatment of edematous states that causes hypokalemia may be supplemented with:
a potassium-sparing diuretic like spironolactone
Aldactone (Spironolactone)
- Potassium-sparing diuretic, aldosterone receptor antagonist
- inhibits binding of aldosterone in the late DCT and collecting duct, which prevents expression of sodium channels.
- Used in combination with other diuretics to prevent hyperkalemia, in treatment of primary hyperaldosteronism, and in PCOS as an anti-androgenic
- Adverse effects; gynecomastia and infertility in men, hyperkalemia.
Osmotic diuretics are primarily used to manage: (list 2)
glaucoma and cerebral edema
Mannitol
- osmotic diuretic
- increases filtrate osmolarity, drawing additional fluid into urine and causing diuresis
- Used in treatment of cerebral edema, increased intraocular pressure (glaucoma), and to icrease urine volume
Diamox (Acetazolamide)
- Carbonic anhydrase inhibitor, diuretic
- Inhibits Carbonic anhydrase at the PCT, which causes increased bicarbonate excretion and a weak diuretic effect
- may cause a secondary metabolic acidosis
- used in treatment of glaucoma, acute mountain sickness, and epilepsy
Common non-electrolyte side effects of loop diuretics include:
Hyperuricemia, hyperglycemia, and ototoxicity
Name the preferred first-line class of diuretic for treatment of each of the following states:
- Edematous states (cirrhosis, CHF, etc.)
- Hypertension
- Hypokalemia
- Renal impairment
- Glaucoma
- Nephrolithiasis
- High altitude sickness
- Cerebral edema
- Edematous states (cirrhosis, CHF, etc.)
- Loop diuretics
- Hypertension
- Thiazides
- Hypokalemia
- K+ - sparing
- Renal impairment
- Loop
- Glaucoma
- CAIs
- Nephrolithiasis
- thiazides
- High altitude sickness
- CAIs
- Cerebral edema
- osmotic diuretics
Carbonic anhydrase inhibitors cause increased excretion of _________ and may therefore cause a matabolic ________
Carbonic anhydrase inhibitors cause increased excretion of bicarbonate** and may therefore cause a metabolic **acidosis
Suggest two ways in which thiazide diuretics provide a therapeutic effect in hypertension
in early treatment they lower BP through natriuretic diuresis. With prolonged treatment there is a decrease in sodium in arteriolar smooth muscle cells, causing vasodilation and decreased PVR
Describe how potassium-sparing diuretics are used in the management of hypertension
Potassium-sparing diuretics are highly effective anti-hypertensives, but also have a relatively high rate of adverse events, so they are used in hypertension not already managed with 3 other drugs.
The four major classes of antihypertensive agents are:
- Diuretics
- Sympatholytics
- Angiotensin inhibitors (ACEIs or ARBs)
- Vasodilators (CCBs, minoxidil)
Blood Pressure = ______ X ______
Blood Pressure = Cardiac Output (CO) X Systemic Vascular Resistance (SVR)
An advantage of using thiazides in the management of hypertension is they protect against _______
osteoporosis
thiazide diuretics reduce the rate of calcium excretion
Loop diuretics are preferred for treating hypertension in individuals with _______ (normal / reduced) kidney function
reduced
α1 - blockers used in management of hypertension may cause “first dose” _______
syncope
Minipress (Prazosin)
- α1 - blocker, sympatholytic, anti-adrenergic
- used to manage hypertension by decreasing SVR
- Generally a second-line treatment, used in combination with a diuretic (diuretic required due to RAAS activation)
- may cause reflex sympathetic activation (resulting in increased CO), orthostatic hypotension, or “first dose” syncope
Aldomet (Methyldopa)
- centrally-acting sympatholytic antihypertensive, selective α2 - agonist
- inhibit sympathetic outflow from the CNS, causing vasodilation and some reduction in CO
- too many side effects compared to other drugs, especially immunologic effects. Used only when other options are ineffective. Also used in pregnancy
Inderal (Propranolol)
- Non-selective β-antagonist (beta-blocker)
- Primarily given orally but may be given parenterally
- One of the first developed and thus has the ridest range of approved clinical uses
- hypertenion, angina, cardiac dysrhythmias, migraine, AMI, pheochromocytoma
- Has more CNS side effects than other non-selective beta-blockers
Tenormin (Atenolol)
- Selective β1-antagonist (beta-blocker)
- oral or parenteral
- good antihypertensive, antianginal, antiarrhythmic
- Low rate of CNS side effects due to poor lipid solubility
Brevibloc (Esmolol)
- Selective β1-antagonist (beta-blocker)
- IV-only!
- good antihypertensive, antianginal, antiarrhythmic
- very short half-life compared to other beta-blockers, used in emergent settings (check out that trade name!)
Lopressor (Metoprolol)
- Selective β1-antagonist (beta-blocker)
- oral or parenteral
- good antihypertensive, antianginal, antiarrhythmic
- relatively short half-life (3-4hr)
Under what conditions are Beta-blockers (beta-antagonists) the preferred drugs in the management of hypertension
hypertension in the context of cardiovascular disease, otherwise CCBs or angiotensin inhibitors are preferred
Calcium channel blockers are better ________ (arteriole / venous) vasodilators
arteriole
they therefore decrease SVR without decreasing preload as much
Nipride (Nitroprusside)
- Nitric Oxide donor, vasodilator, antihypertensive
- Causes smooth muscle relaxation in arterioles and veins
- short half-life and time of onset
- Used in hypertensive emergencies
- Prolonged use may lead to cyanide and thiocyanate toxicity
Suggest a treatment strategy for a patient with stage 1 hypertension (SBP 140-159)
- lifestyle modifications
- Drug monotherapy (likely Angiotensin inhibitor or CCB due to low side-effect risk)
Suggest a treatment strategy for a patient with stage 2 hypertension (SBP >160)
- lifestyle modifications
- Drug therapy with at least 2 medications, often starting with CCBs and angiotensin inhibitors, perhaps adding a thiazide diuretic or beta-blocker
- Trial new drug combinations for several weeks before switching treatment
Centrally-acting sympatholytics are rarely used to treat hypertension, but may be useful in: (list 2)
- hypertensive emergencies in an outpatient setting (one dose provides lasting effect)
- pregnancy (methyldopa does not harm the fetus)
identify the differences between the various classifications of angina
- Typical angina involves narrowing of coronary artery lumens by atherosclerotic plaques and is seperated into stable and unstable
- Stable angina occurs with exertion/sympathetic activation
- Unstable angina occurs at rest and varies in intensity, frequency, and duration. Caused by thrombotic occlusion and may lead to MI
- Variant/Prinzmetal angina is due to coronary artery spasm and is prolonged and cyclic
The cause of angina is ________
myocardial hypoxia
Drugs to treat angina generally work by: (list 2)
- decreasing myocardial oxygen demand
- increasing myocardial oxygen supply
Use the provided chart to organize the antianginal drugs
Use the provided chart to organize the antihypertensive drugs
Organic nitrites and nitrates are useful in which forms of angina?
All forms of angina
CCBs are useful in which forms of angina?
Stable typical angina and variant angina. CCBs are not useful in MI or unstable angina
β - blockers are useful in which forms of angina?
all forms of typical angina, especially in MI. Not useful in atypical/prinzmetal angina
Nitrostat (Nitroglycerin)
- Nitrate antianginal
- Increases NO concentrations near vascular smooth muscle, which leads to increased cGMP production and venous vasodilation.
- Causes a decrease in preload and myocardial oxygen demand. In higher doses has arteriolar effects, resulting in decreased afterload
- May cause drop in SBP and reflex tachycardia
Explain how nitrates reduce myocardial workload and oxygen demand
nitrates primarily cause venous vasodilation which reduces preload and myocardial wall tension
A danger of prolonged administration of nitrates is _________
development of tolerance
nitrates are primarily ________ (arteriolar / venous) vasodilators
venous
which CCBs have the greatest vasodilatory effect relative to cardiac effect?
the dihydropyridine (those that end in -pine) CCBs. For example; amlodipine, felodipine, nifedipine
How do CCBs help relieve angina?
- All CCBs cause smooth muscle relaxation and therefor increase coronary blood flow, and also may decrease cardiac workload.
- Diltiazem and verapamil also have a higher affinity for cardiac calcium channels and are negative inotropes and chronotropes, so they must be used with cuation in heart failure
Which CCBs must be used with caution in heart failure and why?
Diltiazem and especially Verapamil, due to their negative inotropic and chronotropic effects.
Adalat (Nifedipine)
- Calcium channel blocker (CCB), antianginal, antihypertensive
- dihydropyridine CCB, therefore has primarily vasodilatory effects
- may cause reflex tachycardia
- As an antianginal, increases coronary perfusion and reduces afterload
- Short half-life, but may be given as a sustained-release formulation once daily
Isoptin (Verapamil)
- Calcium-channel blocker, antianginal, antiarrhythmic
- Has the strongest cardiac effect of the CCBs
- Useful in stable and variant angina
- Must be used with caution in heart failure due to its negative inotropic and chronotropic effect
Cardiazem (Diltiazem)
- Calcium-channel blocker, antianginal, antiarrhythmic
- Has an intermediate cardiac effect (more than nifedipine, less than verapamil)
- Useful in stable and variant angina
- Must be used with caution in heart failure due to its negative inotropic and chronotropic effect
CCBs act on _________ (arterial / venous / both) smooth muscle
arterial only!!
How do CCBs provide an antianginal effect? (list 3 ways)
- they increase coronary blood flow (arteriolar vasodilation)
- they decrease afterload (arteriolar vasodilation), thereby reducing cardiac wall tension and oxygen demand
- The non-dihydropyridines (diltiazem, verapamil) have negative chronotropic and inotropic effects which reduce workload
How do β1-blockers provide their anti-anginal effect?
They reduce cardiac ischemia by preventing exercise-induced tachycardia and may prevent reflex tachycardia caused by other antianginals (esp. nitrates and dihydropridine CCBs)
Why should β1-blockers be used in caution in patients with heart failure? What drugs might potentiate this effect?
because they are negative inotropes. This could be potentiated by verapamil, and to a lesser degree, diltiazem.
The hallmark of heart failure is _________
reduced stroke volume and cardiac output
List common changes that occur as a result of cardiac/ventricular remodelling
- Wall thickening (hypertrophic) or thinning (dilated)
- Cardiac narrowing (hypertrophic) or dilatation (dilated)
- Interstitial fibrosis
- Cardiac wall stiffening
Describe how neuroendocrine responses can exacerbate heart failure
- SNS activation, RAAS, Inflammatory cytokines attempt to restore CO by Frank-Starling mechanism
- Leads to an increase in cardiac remodelling (incr. wall stiffness, fibrosis, hypertrophy/thinning, dilation/narrowing)
- RAAS activation leads to incr. PVR and blood volume, incr. workload on myocardium
β1-blockers ________ (do / do not) improve mortality in unstable angina
DO
Goals of treatment in heart failure are:
- improve symptoms
- slow or reverse deterioration
- prolong survival / reduce mortality
The 3 major strategies to treat heart failure, and the classes of drugs used in each are:
- Increase cardiac output
- positive inotropes
- vasodilators
- Reduce pulmonary and systemic congestion
- vasodilators
- diuretics
- Slow or reverse cardiac remodelling
- angiotensin inhibitors
- sympatholytics
The three classes of inotrope used in the management of HF are:
- cardiac glycosides
- adrenergic agonists
- PDE3 inhibitors
Describe the MOA and role of digoxin in the management of HF
- Digoxin inhibits the action of the Na/K pump, increasing intracellular sodium, which activates the sodium-calcium exchanger. This increases intracellular calcium. Also inihibits sympathetic activity
- Decreases AV nodal conduction, positive inotrope
- Generally used to treat heart failure associated with A Fib
Digoxin has a _______ (low / high) therapeutic index
LOW!
adverse effects include arrhythmias, GI disorders, hallucinations, seizures. Antidote is digoxin-immune Fab.
Lanoxin (Digoxin)
- Cardiac Glycoside, antiarrhythmic
- used in treatment of A Fib and HF
- inhbits Na/K pump and increases intracellular Ca through Ca/Na exchanger
- negative chronotrope and positive inotrope
- LOW therapeutic index
What is the advantage of using dobutamine in treating HF vs. other adrenergic agonists
it improves SV with little to no increase in HR
Adrenergics and PDE3 inhibitors are used in __________ (acute / chronic) heart failure
Acute!
these drugs may cause angina, increased myocardial workload, tolerance, and other adverse effects.
Primacor (Milrinone)
- type 3 phosphodiesterase inhibitor (PDI), positive inotrope
- increases cAMP and therefore Ca2+ concentration in cardiomyocytes
- used in acute heart failure when other inotropes are ineffective.
Describe the roles of Angiotensin inhibitors (ACEIs and ARBs) in the management of heart failure
they reduce both preload (reduces congestion) and afterload (improves SV) while slowing cardiac remodelling. ARBs are generally less effective in HF than ACE inhibitors
Common drug types used in the management of acute heart failure are:
- IV vasodilators (nitrates/hydralazine)
- Diuretics
- Inotropic agents, esp. Dobutamine and Milrinone
- Oxygen
Common management of chronic systolic heart failure generally includes 3 classes of drugs:
A diuretic (loop), an angiotensin inhibitor, and a β - Blocker. Aldosterone antagonists may be added as needed
Use the table provided to organize drugs commonly used in managing heart failure
Which Beta-blockers have been shown to reduce mortality in heart failure?
carvedilol, metoprolol, bisoprolol
Describe the MOA of nitric oxide donors in management of angina and hypertension
NO donors increase local concentrations of NO, which triggers increased intracellular cGMP production. cGMP causes decreased intracellular Ca2+ concentration which brings about smooth muscle relaxation and vasodilation
What determines the level of Ca2+ in cells? How does this differ between different cell types?
- cAMP concentration determines Ca2+ level
- In cardiomyocytes and pacemaker cells, cAMP levels correlate positively with Ca2+ concentration. The opposite is true in smooth muscle cells explaining how the same types of receptor (Gs GPCRs) can have opposite effects in different cells when stimulated.
- Ex: both beta-1 and beta-2 receptors are Gs GPCRs but have opposite effects on calcium levels when stimulated
Describe the locations and functions of V1 and V2 receptors for ADH
- V1 receptors are found in vascular smooth muscle. Activation causes vasoconstriction
- V2 receptors are found in the basolateral membrane of the kidney tubules. Stimulation leads to aquaporin insertion and increased water retention
- The result of V1 and V2 activation is increased circulating volume and vasoconstriction leading to increased BP
Which class of diuretics are referred to as “low-ceiling” diuretics?
thiazides
Why are beta1-blockers better at reducing BP than alpha1-blockers?
Because alpha1 blockers cause reflex tachycardia, leading to increased CO and BP. Beta1-blockers inhibit reflex tachycardia directly, while alpha1-blockers have no direct cardiac effect.
