Weatherly's Woes - Hypertension

HYPERTENSION

Chronically high blood pressure (>120/70 at 2 different times)

Primary HTN (95%) the cause is unknown. A high salt diet and sleep apnea probably causes a lot of cases, but it’s often hard to prove it in real life.

Secondary HTN (5%) the cause is clear.

- - Renal Artery Stenosis - atherosclerosis blocks blood flow to the kidney(s). The kidney freaks out and releases tons of renin. That jacks up the BP. A renal bruit is heard on exam. Unilateral RAS is asymptomatic, because the other kidney compensates by releasing less renin and peeing more sodium (pressure natriuresis). Bilateral RAS causes severe refractory HTN. Patients are heavily reliant on the effects of Angiotensin II, which constricts the EA to maintain GFR. Drugs that dilate the EA (ACE Inhibitors) or constrict the AA (NSAIDS) may precipitate acute renal failure. The treatment is typically surgical. A rare cause is Fibromuscular Dysplasia (more common in women), which involves non-inflammatory deposition of collagen and junk in the media, resulting in a “string of beads” of stenosis and aneurysms in the renal / carotid arteries. See Kidney section for more details.
  - Pheochromocytoma - a tumor that releases waves of norepi and epi, which episodically jacks up the sympathetic tone. Patients complain of episodic palpitations, anxiety, headache and sweating. On a test, the patient will have really high BP during a flare up. Dx is made by finding catecholamine breakdown products (metanephrines or vanillylmandelic acid) in the urine. Manage the BP with alpha blockers (Phentolamine / Phenoxybenzamine) until the tumor can be removed surgically.
  - Primary Aldosteronism - aldosterone is inappropriately secreted. Sometimes it’s idiopathic. Sometimes it’s due to a secretory adenoma of the adrenal glands (Conn’s Syndrome). Renin is low. Expect hypokalemia. ANP upregulation nullifies some of the effects, so they have euvolemic exams. Use Spironolactone. Liddle’s Syndrome is a genetic increase in the sodium transporter (ENaC) that Aldosterone increases. Similar to Primary Aldosteronism, but the Aldosterone levels are low. Spironolactone doesn’t work, but Amiloride does.
  - Cushing’s - too much cortisol. Either due to corticosteroid therapy, or some tumor ramping up the cortico-adrenal axis. Cortisol raises BP by sensitizing blood vessels to catecholamines.

Hypertensive Urgency - scary high BP, but no symptoms yet. There’s no agreed upon cutoff, but 180/120 is a reasonable threshold.

Hypertensive Emergency - scary high BP that is causing symptoms such as cardiac ischemia (elevated troponin), Renal failure (hematuria, proteinuria) or Neuro damage (papilledema, encephalopathy)

Malignant HTN - a vague term referring to really bad chronic HTN that’s difficult to control. I think of malignant HTN occurring in patients who haven’t seen a doctor in decades. Histologically, it causes onion-skinning around small arteries.

ANTIHYPERTENSIVES, PART 1 (ALPHA & BETA)

Adrenergics

Heads up -- most of these are not first-line for hypertension. But they are indicated for a lot of other cardiovascular problems. I included them first because the adrenergic system is VERY, VERY important. Sympathetic modulation lies at the heart of much of modern medicine. I can’t emphasize the chart on the next page enough!

Beta-Receptors - There are 3 beta receptors, but you can kind of ignore B3, which is only important for metabolism. B1 receptors are in the kidneys (increase renin) and heart (increase HR and contractility). Blocking them lowers the cardiac output (heart) and effective circulating volume (kidneys), both of which will lower the BP. B2 receptors are found in the lungs (bronchodilator) and blood vessels (dilate) of the muscles and liver. Blocking these is often counteractive in the treatment of HTN.

There are 4 types of Beta-Blockers. #1 and #3 are second-line agents for HTN. #2 and #4 aren’t used at all for HTN.

1. 1. B1 Selective Blockers (a.k.a. cardioselective) - Metoprolol, Atenolol and Esmolol. Esmolol is only given IV, and Atenolol is a bad drug (ineffective and can cause diabetes), so Metoprolol is the most important member of this class. They are first line for systolic CHF and second-line for HTN.
  2. B1/B2 Nonselective Blockers - Propranolol, Timolol and Nadolol. Shouldn’t be used for HTN.
  3. B1/B2/A1 Blockers - Carvedilol and Labetalol. They are both 2nd line antihypertensives. Carvedilol is more of a CHF drug. But Labetalol is a pretty good antihypertensive in two select instances. (1) In a hypertensive emergency, and (2) in a pregnant woman with hypertensive emergency.
  4. Partial Agonists - low yield

Here are the potential side effects with Beta-Blockers. These are high yield!

- - Lower Heart Rate that occurs in every patient. Most patients on a BB have a HR in the 60s.
  - Fatigue, ED and Depression are commonly attributed to BB’s (particularly Propranolol), but probably aren’t real
  - Mild Hypoglycemia. Epi raises glucose. BB’s interfere with epi.
  - Very Mild Hyperlipidemia. Not super clinically relevant.
  - “Masking Hypoglycemia” - the brain uses the SNS to tell the body that it’s hypoglycemic, by quickly raising the SNS tone to cause symptoms like palpitations, anxiety and diaphoresis. But BB’s block that signal. So if a diabetic on Metoprolol becomes hypoglycemic, they often won’t realize it until they have a seizure out of the blue. However, one symptom will occur -- sweating -- which is mediated by Muscarinic receptors, not adrenergic ones. So just be careful in patients with diabetes. You should still give them BBs, because BBs are awesome drugs, but just educate your patient.
  - Wheezing is common with the nonselective BBs (Propranolol), because blocking B2 receptors causes bronchoconstriction. Nonselective BBs should be avoided in asthma / COPD (not that you would use them to treat HTN in the first place!!)
  - Potentially worsens Decompensated CHF. Blocking B1 lowers the cardiac output. Usually this helps the heart so much that it outweighs the decreased peripheral perfusion, but if the cardiac output is already dangerously low then BBs can make the situation worse
  - Overdose - cardiogenic shock with pronounced bradycardia and AV blocks. Glucagon is the antidote, which activates cAMP in heart cells via different receptors.

Alpha-1 Blockers (Doxaosin) vasodilate. That lowers the TPR. For whatever reason, they’ve fallen out of favor as a treatment for HTN. Nowadays, they’re usually used to dilate the ureter in BPH or a kidney stone (Tamsulosin is particularly uroselective). The side effect is postural hypotension.

Alpha-2 Agonists lower the sympathetic tone. Clonidine is the oldest antihypertensive. It isn’t used too much anymore. On the plus side, it’s very fast acting. It causes a lot of sedation. And when patients stop taking it, they experience a huge rebound hypertension (fast onset, fast offset). Methyldopa is one of the few antihypertensives that’s safe and well-studied during pregnancy. Rarely, it can cause lupus-like syndrome or IgG (warm) Autoimmune Hemolytic Anemia.

ANTIHYPERTENSIVES, PART 2 (CALCIUM CHANNEL BLOCKERS)

Calcium Channel Blockers

Calcium Channel Blockers work by relaxing smooth muscles. Blood vessels are surrounded by smooth muscle, hence how CCBs work. There are two kinds of CCBs

Dihydropyridines like Amlodipine are first line antihypertensives. They lower the BP by vasodilating arterioles. Makes sense! HTN is pretty much the only indication for these bad boys (sometimes angina too). They’re really safe, effective and well tolerated. But potential SEs include flushing or headache from the vasodilation. It may potentially cause or worsen lower extremity pitting edema by opening up the floodgates (arterioles) to the capillaries, increasing the capillary hydrostatic pressure. Nifedipine is the only CCB safe during pregnancy.

The Cardiac CCBs (aka the non-Dihydropyridines) are Verapamil and Diltiazem. They’re useful in (you guessed it) heart problems, but not so much for hypertension. They’re pretty easy to remember, because their effects are really similar to the Cardioselective Beta-1 Blockers (Metoprolol). They lower chronotropy and inotropy, which eases the workload of the heart and can suppress arrhythmias (Class 4). Note that Verapamil is “more cardiac” than Diltiazem, but idk if that matters. Both of ‘em cause bradycardia and AV blocks. Verapamil has side effects of constipation and gingival hyperplasia (also seen with Phenytoin and Cyclosporine).

ANTIHYPERTENSIVES, PART 3 (RAAS)

ACEs and ARBs

RAAS drugs are almost always first line with HTN. They’re super effective and really safe. They’re also a first line treatment for CHF, and they slow down the kidney damage that occurs in diabetes.

ACE Inhibitors (-pril) block the conversion of Angiotensin I to Angiotensin II. ACE also breaks down the pro-inflammatory molecule Bradykinin, and Bradykinin surplus leads to a chronic dry cough (10%) and angioedema (<5%). Angioedema means swelling of the face (this isn’t the technically correct definition, but this is how you should think of it). Angioedema is bad because the swelling can get bad enough to obstruct the mouth or throat! In situations of severe angioedema, you should intubate! Angioedema can happen at any time to any patient taking it. ACE Inhibitors also tend to raise potassium a bit.

Angiotensin Receptor Blockers (-sartan) or ARBs block the effects of Angiotensin II. Clinically identical to the ACE Inhibitors, but without that Bradykinin nonsense here (so no angioedema or cough).

Aliskiren blocks the activity of Renin. This one is newer, and more expensive, although early evidence is quite promising.

Other Antihypertensives

Hydrochlorothiazide is the only diuretic currently used to treat HTN. It blocks Na+ reabsorption in the distal convoluted tubule.

Hydralazine directly opens up arteries. It lowers the afterload. It’s rarely used for HTN. It is safe in pregnancy though. SEs include a lupus-like syndrome (similar to Procainamide). Historically, Hydrochlorothiazide and Hydralazine have been preferentially used in the Black population instead of ACE-Inhibitors; however, this practice has come under a lot of scrutiny lately.

Hypertensives that are safe during pregnancy -- Nifedipine, Hydralazine, Methyldopa and Labetalol.