133 Hypertension Flashcards
Prevalence of hypertension
1 in 4 adult americans
smoking is a worse factor of CVD than hyptertension
Classifications of hypertension
Consensus treatment of blood pressure guidelines
factors that affect BP
- volume
- cardiac output
- peripheral vascular resistance
Volume receptors (high, low)
High Pressure: Carotid sinus, aortic arch, left ventricle, and the juxtaglomerular apparatus
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Low Pressure: Cardiac atria, right ventricle, and pulmonary vessles
Effectors: RAA, Sympathetic nerves, ANP, ADH, Pressure natriuresis
Effect: Urine Na+ excretion
•Regulation of sodium, predominantly by the kidney, controls the volume of the extra-cellular compartments (intravascular)
Diuretics: Distal Convoluted Tubule
- •Class often called Thiazides because hydrochlorothiazide is the most well known and recognized
- -Hydrochlorothiazide (HCTZ), Chlorthalidone, Metolazone
- •Inhibit the Na – Cl symporter in the distal convoluted tubule.
- •Side effects: Impotence, fluid and electrolyte imbalances, impaired glucose tolerance, and increased cholesterol
- Hypokalemia, hyponatremia, hypercalcemia
- Shown to decrease cardiovascular morbidity and mortality (low doses that do not cause hypokalemia). A first line treatment option for hypertension.
Thiazides example SOAP
Diuretics: Loop
- •Agents: Furosemide (Lasix), Torsemide (Demadex), Bumetanide (Bumex)
- •Inhibit the Na+-K+-2Cl- symporter in the thick ascending limb of the loop of Henle.
- •Side effects: Fluid and electrolyte imbalances, volume depletion, ototoxicity, hyperuricemia, hyperglycemia, increased LDL and triglycerides
- -Hypokalemia, hypocalcemia, and hypomagnesemia
- Used for volume overload (rapid diuresis). Used for HTN particularly in chronic kidney disease. Can also be used with normal saline to treat hypercalcemia. Used for Heart Failure fast.
Loop Diuretics SOAP
Diuretics: K+ Sparing
- Agents: Triamterene, Amiloride, Spironolactone, Eplerenone
- Mechanism: Triamterene and Amiloride inhibit renal epithelial Na+ channels in the late distal tubule and collecting duct. Spironolactone and Eplerenone antagonize the mineralocorticoid receptor on epithelial calls in the late distal tubule and cortical collecting duct.
- Happens at Principal Cell in collecting tubule (main job is to absorb Na+)
Side effects:
- Amiloride and Triamterene: Hyperkalemia, nausea, vomiting
- Spironolactone: Hyperkalemia, gynecomastia
- Adjunctive treatments with diuretics to avoid hypokalemia. Use caution if at risk for hyperkalemia.
Potassium Sparing Diuretics SOAP
Spironolactone
Amiloride
General effect of diuretics on body (leading mechanism) + Summary info
- Lower blood pressure by decreasing intravascular volume (and cardiac output). With chronic use, they promote vasodilation.
- Main side effects are electrolyte abnormalities and volume depletion.
- Drug interactions center on exacerbation of electrolyte abnormalities or volume depletion.
- Distal convoluted tubule diuretics (thiazides) have been shown to lower blood pressure and decrease cardiovascular morbidity and mortality. They are first line agents for many patients.
- •If the proximal tubule absorbs > 60 of sodium, why are proximal tubule diuretics not good for hypertension ?
- •Which is better for hypertension, a loop diuretic or a thiazide diuretic ?
- •Will a diuretic make a person urinate more ?
•If the proximal tubule absorbs > 60 of sodium, why are proximal tubule diuretics not good for hypertension ?
-When kidney senses lots of sodium loss at PCT the other parts (DCT and OMCD) rev up so net loss Low
•Which is better for hypertension, a loop diuretic or a thiazide diuretic ?
-Loop diuretic acute aggressive volume loss, thiazide better for uncomplicated patient for controlling chronic HTN
•Will a diuretic make a person urinate more ?
-First couple days you lose 5% volume, but after then you shouldn’t be peeing any more
Renin Angiotensin System overview and players
Aldosterone:
- •Aldosterone is produced by the Zona Glomerulosa of the Adrenal Cortex
- •It acts in the distal nephron to cause Na+ absorption, and K+ and H+ excretion
Drugs Affecting the Renin-Angiotensin System
•Angiotensin Converting Enzyme Inhibitors:
- Captopril, enalapril, lisinopril, quinapril, ramipril, benazepril, fosinopril …
-Mech: Block the conversion of angiotensin I to the active angiotensin II by inhibiting angiotensin converting enzyme.
•Angiotensin II Receptor Blockers:
-Losartan, candesartan, irbesartan, valsartan …
Mech: -Block the Angiotensin II receptor. There are two angiotensin II receptors (referred to as AT1 and AT2), and the ARBs in current use block the type 1 receptor (AT1). The type 1 receptor is found in myocardial tissue, brain, kidney, smooth muscle cells, and adrenal glomerulosa cells.
Angiotensin converting enzyme inhibitors (ACE-I):
Angiotensin converting enzyme inhibitors (ACE-I):
-Block the conversion of angiotensin I to the active angiotensin II by inhibiting angiotensin converting enzyme.
Captopril, enalapril, lisinopril, quinapril, ramipril, benazepril, fosinopril
Renin Angiotensin System:
Effect of ARB
- Block the Angiotensin II receptor. There are two angiotensin II receptors (referred to as AT1 and AT2), and the ARBs in current use block the type 1 receptor (AT1). The type 1 receptor is found in myocardial tissue, brain, kidney, smooth muscle cells, and adrenal glomerulosa cells.
- Losartan, candesartan, irbesartan, valsartan …
Side effects of ACE-Is and ARBs
- •ACE-I: Cough, hyperkalemia, renal failure, fetal toxicity, angioedema
- •ARBs: Hyperkalemia, renal failure, fetal toxicity. Rare angioedema, no cough.
- •Why is there no cough, much less angioedema with ARBs?
- -Less Bradykinin
increased risk of birth defects with ACEs and ARBs
ACE-I/ARB SOAP
- •Hypertensive patients, particularly:
- -Patients with heart failure
- -Patients with diabetes/proteinuria
- -Patients with CAD/post MI
- •Excellent adjunctive agents (particularly diuretics)
- •ARBs have an excellent side effect profile, many are now generic
•Thinking of electrolytes, why do ACE-I (or ARBs) work well with thiazide type diuretics?
Similarly, what would you have to watch for when using ACE-I (or ARB) with potassium sparing diuretics?
•Thinking of electrolytes, why do ACE-I (or ARBs) work well with thiazide type diuretics?
-Thiazide cause more sodium delivery to distal part of kidney which is exchanged for potassium so you get hypokalemia, but ACE-I cause this exchange to happen less so you get hyperkalemia, so using both gives happy medium
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•Similarly, what would you have to watch for when using ACE-I (or ARB) with potassium sparing diuretics?
-Potassium sparing will cause you to hold on to K, and ACE-I also reduce the exchange and casue hyperK so watch for this!
Centrally Acting Agents Hypertension
- Agents: Methyldopa, clonidine, guanabenz, guanfacine
- Mechanism:
- Methyldopa replaces norepinepherine in the secretory vesicles of adrenergic neurons. Although it is a potent vasoconstrictor, it acts centrally on the brain to inhibit central adrenergic outflow.
- Clonidine (guanbenz, guanfacine) stimulates the centrally located α2-receptor
SIDE EFFECTS:
•Methyldopa: Sedation, dry mouth, decreased energy, depression, liver toxicity
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•Clonidine, Guanabenz, Guanfacine: Sedation/somnolence, dry mouth, depression, bradycardia. Can get withdrawal symptoms (headache, HTN, tremors, sweating) if high dose is stopped suddenly.
SUMMARY:
•The centrally acting agents work by central inhibition of adrenergic outflow.
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•Side effects are primarily CNS related, and prevent them from being first line agents
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•Useful adjunctive agents with minimal interactions with other drug
Methyldopa
-Methyldopa replaces norepinepherine in the secretory vesicles of adrenergic neurons. Although it is a potent vasoconstrictor, it acts centrally on the brain to inhibit central adrenergic outflow.
Side effect: •Methyldopa: Sedation, dry mouth, decreased energy, depression, liver toxicity
Population: •Well established agent, particularly in pregnancy. Side effects make it an alternative option.
Clonidine
-Clonidine (guanbenz, guanfacine) stimulates the centrally located α2-receptor
Side effects: •Clonidine, Guanabenz, Guanfacine: Sedation/somnolence, dry mouth, depression, bradycardia. Can get withdrawal symptoms (headache, HTN, tremors, sweating) if high dose is stopped suddenly.
Population: •Clonidine – Side effects cause this agent to be used adjunctively. Minimal interactions with other agents make it useful add on therapy.
Centrally Acting Sympatholytic Agents SOAP
Sympatholytics:
α1-receptor Blockers
- Agents: Prazosin, terazosin, doxazosin
- Mechanism of Action: Blocks the α1- receptor
Alpha1 Blockers SOAP
What are main differences between centrally acting symptholytics (e.g. clonidine) and peripherally acting agents (e.g. alpha blockers) ?
- Side effect profile – centrally acting has CNS side effects (depression, fatigue)
- Centrally acting may suppress cardiac output, peripherally acting may increase cardiac output (both will relax blood vessels, and cause volume retention in the more relaxed blood vessels)
ß-Blockers
•Agents:
- Atenolol, Metoprolol – ß1 selective (little ß2 activity)
- Propanolol, Timolol – ß1 and ß2
•Labetalol and Carvedilol block beta receptors as well as have some alpha-1 blocking activity
•Mechanism of action: Block receptors –
- ß1 – Cardioselective – Tachycardia, increased cardiac contractility, Renin release from JG apparatus
- ß2 – Bronchodilation, slight decrease in peripheral vascular resistance (slight vasodilation)
•Side Effects: Bradycardia, hyperkalemia, fatigue, cold extremities, and bronchospasm. May have adverse effect on lipid panel, and blunt symptoms of hypoglycemia.
•Population: Preferably in patients with CAD (MI, Angina, post- CABG). Not for sole use in a patient with hypertension and heart failure.
-Some agents have intrinsic sympathomimetic (partial agonist) activity. Some agents also block α1-receptors (labetalol, carvedilol). Carvedilol is particularly popular for heart failure.
Summary:
- Decrease blood pressure by blocking β-receptors, which decreases cardiac output.
- β-blockers have varying degrees of affinity for the various β receptors.
- Main side effects are bradycardia and fatigue. Some harbor concerns when giving these agents to asthmatic patients and diabetic patients.
- Not recommended as sole treatment. Felt particularly useful with CAD (angina, CAD, Post MI or post CABG). Excellent adjunctive agent, particularly with drugs that increase sympathetic discharge (peripheral vasodilators, diuretics).
Effect of stimulation and blockade of each of B1 and B2 receptors
alpha1 receptor blockers mech
•Labetalol and Carvedilol block beta receptors as well as have some alpha-1 blocking activity
B-blockers SOAP
Mechanism of vasoconstriction
Via: Ca+2 modulation
Note: both the angiotensin 1 (AT1) receptor and the adrenergic receptor (α1) increase intracellular calcium
We can also block Ca+ channel via Ca-channel agonists:
- •Phenylalkylamines (Verapamil – like)
- •Benzothiazepine (Diltiazem – like)
- •Dihydropyridine (Nifedipine – like)
- -Many other agents (Amlodipine, felodipine, nisoldipine, nitrendipine, nicardipine)
Calcium Channel Blockers (3)
•Mechanism of action: All calcium channel blockers (CCBs) block the L-type calcium channel preventing the influx of calcium.
•Since the contraction of the smooth muscle is dependent on calcium, less intracellular calcium results in less contraction, which decreases the peripheral vascular resistance.
Agents:
- Phenylalkylamines (Verapamil – like)
- Benzothiazepine (Diltiazem – like)
- Dihydropyridine (Nifedipine – like), Many other agents (Amlodipine, felodipine, nisoldipine, nitrendipine, nicardipine)
Population:
- Safe in patients with diabetes, renal insufficiency, lipid problems, and asthma.
- Use with caution (particularly the more cardioselective agents) in patients with heart failure and conduction abnormalities.
- Possibly synergistic with other agents, therefore good add-on therapy.
Summary:
- Lower blood pressure by blocking Ca+ channel. Have differing amounts of cardiac and vascular affinity.
- Side effects associated with mechanism of action (blocking smooth muscle contraction – flushing, headaches, GI complaints)
- Interactions relate to metabolism via CP-450 pathway or additive effects of agents that work similarly
- Proven to lower blood pressure effectively (African American, elderly), and safe in multiple populations. Perhaps synergistic with other agents.
CCBs: Dihydropyridine
•Agents: Nifedipine, amlodipine, felodipine, nisoldipine, nitrendipine
•Mechanism: Block Ca+ channels, predominantly in vascular smooth muscle
•Side Effects: Headaches, flushing, dizziness, GERD, constipation, peripheral edema
•Interactions: Metabolized by CP-450 system. Usually do not alter metabolism of other drugs. Grapefruit juice may increase bioavailability.
CCBs: Benzothiazepine
•Agent: Diltiazem
•Mechanism: Blocks Ca+ channels, both in vascular smooth muscle and in the heart.
•Side Effects: Edema, headache, nausea, dizziness, constipation, diarrhea, bradycardia
•Interactions: Metabolized by the CP-450 system. May inhibit clearance of other drugs (e.g. benzodiazepines, HMG CoA reductase inhibitors, Cyclosporin)
CCBs: Phenylalkylamine
•Agent: Verapamil
•Mechanism: Blocks Ca+ channels, predominantly in the heart, but has some effect on vascular smooth muscle.
•Side effects: Constipation, dizziness, nausea, bradycardia
•Interactions: Metabolized by the CP-450 system. May inhibit clearance of other drugs (e.g. benzodiazepines, HMG CoA reductase inhibitors, Cyclosporin). Use caution (avoid if possible) with other agents that slow heart rate or are antiarrhythmic. Can increase digoxin levels.
Calcium Channel Blockers SOAP
Peripheral Vasodilators SOAP
Peripheral Vasodilators:
Mechanism of Action
•Hydralazine: Lowers blood pressure through relaxation of arteriolar smooth muscle.
•Minoxidil: Activates a potassium channel in vascular smooth muscle, causing K+ efflux. This efflux hyperpolarizes and relaxes the smooth muscle cells.
•Nitroprusside: Metabolized by blood vessels to nitric oxide. Nitric oxide activates guanyl cyclase which makes cGMP and vasodilates the blood vessels.
Side Effects:
•Hydralazine: Headache, nausea, flushing, dizziness, angina, edema/heart failure.
-Immunological – drug induced lupus.
- Minoxidil: Na+ and H2O retention, tachycardia/angina/heart failure, hypertrichosis, effusions
- Nitroprusside: Hypotension. Cyanide and thiocyanate toxicity, manifests as severe lactic acidosis, anorexia, fatigue, confusion, psychosis.
Population:
- Used in patients with difficult to control blood pressure. These patients are often on multiple agents, which allows some control of the side effects of the vasodilators ( β- blockers, diuretics).
- Hydralazine available I.V. or P.O., Nitroprusside is only available I.V., Minoxidil available P.O.
Summary:
- Decrease blood pressure by dilating blood vessels.
- Side effects relate to vasodilation, and reflex sympathetic activity from that vasodilation.
- Useful in patients who have difficult to control hypertension. IV forms useful in hypertensive emergencies.
Hydralazine
•Hydralazine: Lowers blood pressure through relaxation of arteriolar smooth muscle.
•Side Effects:
•Hydralazine: Headache, nausea, flushing, dizziness, angina, edema/heart failure.
-Immunological – drug induced lupus.
•Hydralazine available I.V. or P.O., Nitroprusside is only available I.V., Minoxidil available P.O.
Minoxidil
•Minoxidil: Activates a potassium channel in vascular smooth muscle, causing K+ efflux. This efflux hyperpolarizes and relaxes the smooth muscle cells.
Side Effects:
•Minoxidil: Na+ and H2O retention, tachycardia/angina/heart failure, hypertrichosis, effusions
Minoxidil available P.O.
Nitroprusside
•Nitroprusside: Metabolized by blood vessels to nitric oxide. Nitric oxide activates guanyl cyclase which makes cGMP and vasodilates the blood vessels.
Side Effects:
•Nitroprusside: Hypotension. Cyanide and thiocyanate toxicity, manifests as severe lactic acidosis, anorexia, fatigue, confusion, psychosis.
Nitroprusside is only available I.V.
Types of Hypertension: Hypertensive Emergency
- Hypertensive Emergency – target organ damage (eyes – retinopathy, heart – chest pain, shortness of breath, kidneys – renal failure, proteinuria) associated with a high blood pressure
- > 180/120 (?)
- Note, high blood pressure, no target organ damage, can be called an “urgency”
White Coat, Masked HTN
White coat Hypertension – high BP in office, controlled at home (~ 20 %)
Masked Hypertension – controlled BP in office, high at home (~ 20 %)
New guidelines focus on obtaining home BPs
Primary vs Secondary HTN
•Primary Hypertension – also called essential – is due to many factors (gentic, environment) and there is no (yet) identified main cause. Accounts for 95 % of hypertension
•Secondary hypertension – there is a specific driver of the hypertension – i.e. an identifiable cause that can cure or markedly improve the blood pressure if identified and treated
