Management of Hypertension

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Terazosin: Problems minor

"First dose phenomenon" - orthostatic hypotension and syncope particularly with first dose (most common with the prazosin but can also occur with other alpha1 adrenergic antagonists).

Hypertension Treatment Strategies: Secondary agents

(indicated with specific conditions or add on when first line is insufficient) Diuretics - Loop, K+ sparing (including mineralocorticoid antagonists) - (cover in Renal/Respiratory) Sympatholytics - β-blockers, combined α1 -β-blockers (previously first-line) - α1-blockers, CNS acting, PNS modifiers - Know: propranolol, metoprolol, esmolol, labetalol, terazosin, clonidine Direct Vasodilators - Know: hydralazine, nitroprusside Direct Renin Inhibitor - (cover in Renal/Respiratory)

Phentolamine: mechanism of action

(nonselective alpha antagonist) -> decrease TPR via a1 antagonism -> activate baroreceptor reflex -> increase NE release into myocardium -> increase heart rate via b1 receptors -> antagonism of a2 receptors in myocardium blocks negative feedback -> cardiac overstimulation

Hypertension proportion of US population affected

1/3

Angiotensin-Converting Enzyme (ACE) Inhibitor: Captopril, Lisinopril, (other "-prils"): Of note

ACE-I and ARBs are less effective in African-Americans than other races as monotherapy for hypertension but appropriate for heart failure Angiotensin II can also be produced by other (local - within tissue) peptidases so inhibiting ACE will not eliminate production of all angiotensin II

Younger (<50) white patients respond better to

ACI-I and ARBs and beta blockers Beta blockers not commonly used for monotherapy but provide protection against stroke risk

Angiotensin II AT1 Receptor Blockers (ARBs): Losartan, Valsartan, (other "-sartans"): Of note

ARBs do not inhibit the breakdown of bradykinin as do ACE inhibitors and thus are not associated with the ACE inhibitor persistent cough ACE-I and ARBs are less effective in African-Americans than other races as monotherapy for hypertension but appropriate for heart failure

Vasodilators effects

All relax smooth muscle or arterioles to decrease systemic vascular resistance Sodium nitroprusside and nitrates also relax veins Not first-line: combine with other antihypertensive drugs

An orally administered drug causes significant peripheral vasodilation and a reduction of blood pressure, but does not cause that effect by blocking any adrenergic receptors or by interfering with the normal synthesis or agonist effects of Angiotensin II. The drug lacks any direct cardiac effects, but it often lowers blood pressure quickly enough to cause baroreceptor-mediated reflex cardiac stimulation (tachycardia, etc.). To which one of the following drugs does this description best apply?

Amlodipine

Which of the following is a calcium channel blocker that has the lowest risk of bradycardia?

Amlodipine

Which of the following is beneficial in the treatment of both hypertension and angina?

Amlodipine

A 57-year-old woman is undergoing a femoral popliteal bypass for her peripheral vascular disease. The vascular surgeon wishes to induce a localized arteriolar constriction to help control hemostasis. An increase in the local concentration of which of the following agents will cause systemic vasoconstriction?

Angiotensin II

Terazosin: Clinical use

Benign prostatic hyperplasia (BPH), HTN (not first-line)

Beta Adrenergic Antagonists ("Beta Blockers"): Propranolol, Metoprolol, Esmolol: problems

Bradycardia, negative inotropy, decreased cardiac output, extreme vasoconstriction particularly cold extremities CNS symptoms (sedation, depression), erectile dysfunction Beta blocker withdrawal: abrupt discontinuation can result in exacerbations of hypertension or angina and myocardial infarction Bronchoconstriction (for nonselective antagonist) - use with caution in patients with asthma Many other effects

Angiotensin II AT1 Receptor Blockers (ARBs): Losartan, Valsartan, (other "-sartans"): Action

Competitive antagonist at angiotensin II receptor (AT1)- blocks effects of angiotensin II produced by ACE and by local tissue enzymes other than ACE Reduction in angiotensin II mediated vasoconstriction Decreased peripheral resistance: decreased afterload Decreased aldosterone secretion, decrease salt and water retention, decreased preload Decreased sympathetic activity from angiotensin II stimulation (thus reduce renin release) Decreased myocardial and vascular remodeling Decreased cardiomyoctye apoptosis Reduce total peripheral resistance

Angiotensin-Converting Enzyme (ACE) Inhibitor: Captopril, Lisinopril, (other "-prils"): Beneficial effects

Decreased angiotensin II (potent vasoconstrictor) and increased bradykinin (a vasodilator) - Decreased peripheral resistance: decreased afterload Decreased aldosterone secretion, decrease salt and water retention, decreased preload Decreased sympathetic activity from angiotensin II stimulation (thus reduce renin release) Decreased myocardial and vascular remodeling Decreased cardiomyoctye apoptosis Reduce total peripheral resistance, mean arterial pressure, diastolic blood pressure, systolic blood pressure

Metyrosine: problems

Depletes catecholamines everywhere

Non-dihydropyridines: Verapamil & Diltiazem: Action

Diltiazem: less effective on vascular smooth muscle than dihydropyridines, more effective in heart Verapamil: less effective on vascular smooth muscle than dihydropyridines or diltiazem, more effective in heart

Hypertension treatment goal

Does not self resolve (must treat for life) Goal of treatment: reduce pressure as quickly as possible. Treatment may involve combining drug classes.

Beta Adrenergic Antagonists ("Beta Blockers"): Propranolol, Metoprolol, Esmolol: Clinical use

Due to adverse effects: no longer first-line monotherapy for HTN but still used particularly in conjunction with other treatment and in patients with myocardial infarction, angina, or heart failure May combine with diuretics to mitigate the compensatory increase in renin secretion Other uses: arrhythmia, angina, post-MI, heart failure, migraine prophylaxis (propranolol), glaucoma (timolol), intraoperative hypertension (esmolol preferred due to short half-life)

Reserpine: problems

Expected peripheral adverse effects (orthostatic hypotension, increased GI activity) CNS effects such as sedation, severe depression and suicide in susceptible individuals

Hypertension Treatment Strategies

First Line Therapy (primary agent or combination) Diuretics - Thiazides - Know class effects only ACE Inhibitors - Captopril, lisinopril AT1 Receptor Antagonists (ARBs) - Losartan, valsartan L-Type Ca++ Channel Antagonists (CCBs) - Dihydropyridine (amlodipine) - Non-dihydropyridine (verapamil, diltiazem)

Hypertension Treatment Strategies in Patients with Co-Morbid Conditions: Heart failure with preserved EF First line therapy Sequential therapy

First line therapy: ACEI (or ARB) and beta-blockers after management of volume overload Sequential therapy: NA

Hypertension Treatment Strategies in Patients with Co-Morbid Conditions: Heart Failure with reduced EF First line therapy Sequential therapy

First line therapy: ACEI (or ARB) and beta-blockers after management of volume overload Sequential therapy: aldosterone antagonist if severe HF Hydralazine and isosorbide dinitrate in black patients

Hypertension Treatment Strategies in Patients with Co-Morbid Conditions: DM First line therapy Sequential therapy

First line therapy: ACEI or ARB Sequential therapy: Thiazide CCB or beta-blocker

Hypertension Treatment Strategies in Patients with Co-Morbid Conditions: Chronic Kidney Dx First line therapy Sequential therapy

First line therapy: ACEI or ARB Sequential therapy: none

Hypertension Treatment Strategies in Patients with Co-Morbid Conditions: Coronary Artery Dx acute or chronic First line therapy Sequential therapy

First line therapy: beta-blocker and ACEI (or ARB) Sequential therapy: Thiazide for BP control, CCB for ischemia control

Thiazide Diuretics (Hydrochlorothiazide) Clinical use

First-line monotherapy for mild-moderate hypertension; often combine with sympatholytic agent or vasodilator to reduce fluid Reduce incidence of stroke associated with hypertension Note: maximal antihypertensive effects occurs at submaximal doses for diuresis and adverse effects (increasing dose will increase diuresis and adverse effects without further decrease in blood pressure) Mild chronic heart failure

Angiotensin-Converting Enzyme (ACE) Inhibitor: Captopril, Lisinopril, (other "-prils"): Clinical use

First-line monotherapy: hypertension First line for chronic heart failure patients with left ventricular dysfunction but no edema - significantly improves long-term survival Diabetic renal disease Proteinuric chronic kidney disease (diminish proteinuria and stabilize renal function)

Reserpine: Clinical use

Hypertension but rarely used because of adverse effects

Thiazide Diuretics (Hydrochlorothiazide) Problems

Hypokalemia (can increase risk of ventricular ectopy, ventricular tachycardia, ischemic ventricular fibrillation): counteract with potassium supplement or adding potassium-sparing diuretic

Angiotensin II AT1 Receptor Blockers (ARBs): Losartan, Valsartan, (other "-sartans"): Adverse effects

Hypotension, hyperkalemia, lower rate of angioedema but may still occur, fetal pathologies, reduction in GFR

Vasodilator: Nitroprusside: Action

Increase cGMP resulting in de-phosphorylation of myosin light chain and relaxation of arteries (more than veins) resulting in reduced total peripheral resistance and venous return

Bretylium and Guanethidine: action

Indirect sympathomimetic Displaces NE from vesicle gradually - little effect from released NE Bretylium has less prominent sympathomimetic effect than does guanethidine Release of NE from terminal can lead to hypertensive crisis Also block physiologic release of adrenergic vesicles

A patient with a history of hypertension and diabetes is treated with metformin, hydrochlorothiazide, metoprolol, lisinopril, and pravastatin and presents to the emergency department with a swollen tongue and uvula of acute onset. What is the therapeutic mechanism of action of the patient's medication that is most likely to have caused this presentation?

Inhibition of formation of angiotensin II

Angiotensin-Converting Enzyme (ACE) Inhibitor: Captopril, Lisinopril, (other "-prils"): Action

Inhibits ACE-conversion of angiotensin I to angiotensin II and decreases ACE-degradation of bradykinin

Metyrosine: Action

Inhibits tyrosine hydroxylase Depletes catecholamines everywhere

Hypertension Staging <120 and <80 120-129 and <80 130-139 or 80-89 140-159 or 90-99 >/=160 or >/=100

JNC7: Normal BP Prehypertension Prehypertension Stage 1 hypertension Stage 2 hypertension 2017 ACC/AHA Normal BP Elevated BP Stage 1 hypertension Stage 2 hypertension Stage 3 hypertension

Beta Adrenergic Mixed Antagonists: Labetolol, Carvedilol: Of note

Labetalol is a common choice during pregnancy to manage hypertension

Beta Adrenergic Mixed Antagonists: Labetolol, Carvedilol: clinical use

Labetalol: hypertensive emergencies Carvedilol: heart failure, hypertension

Clonidine, Methyldopa: clinical use

Methyldopa: high blood pressure during pregnancy Clonidine: hypertension (not first-line) as well as others: ADHD, pain, restless legs syndrome

Clonidine, Methyldopa: problems

Methyldopa: sedation Clonidine: sedation, hypertensive crisis with sudden withdrawal (taper dose)

Other Sympatholytics: Less Commonly Used (But Still Tested)

Metyrosine: inhibits synthesis of catecholamines Methyldopa: a2 agonist - Current use: hypertension in pregnancy Clonidine: a2 agonist - Current use: refractory hypertension (may also be part of treatment for hypertensive emergencies) Reserpine: depletes monoamines Guanethedine: chemical sympathectomy

Drugs that Release NO from drug or endothelium

Nitroprusside, hydralazine, nitrates, histamine, acetylcholine

Hypertension cause

No single cause; considered a mosaic disorder involving genetic, diet, vascular and regulatory components

Hypertension Treatment Challenges

Non-compliance - Hypertension is asymptomatic except during end stage pathology - Requires continual, daily drug treatment. - Many anti-hypertensive drugs have undesirable side effects including ED in men, general sexual dysfunction and serious CNS effects (i.e. depression, nightmares, insomnia, schizophrenic tendencies, etc.)

Reserpine: Action

Nonselective, irreversible inhibitor of Vesicular Monoamine Transporter (VMAT) Depletion of NE from vesicles, can cause accumulation in the cytosol and release via reversal of NET

Bretylium and Guanethidine: clinical use

Obsolete - was used in treatment of hypertension

Angiotensin II AT1 Receptor Blockers (ARBs): Losartan, Valsartan, (other "-sartans"): Clinical use

Often used in patients who do not tolerate ACE inhibitors Valsartan - combined with Sacubitril First-line monotherapy for hypertension (often replacement for patients who do not tolerate ACE inhibitors)

Metyrosine: clinical use

Perioperative management of pheochromocytoma (tumor of adrenal medulla that results in excessive epinephrine and norepinephrine synthesis and release) Hypertension (uncommon)

Diltiazam: Peripheral vascular resistance HR SA node AV node Contractility

Peripheral vascular resistance: decrease HR: decrease SA node: decrease X2 AV node: decrease Contractility: decrease

Verapamil: Peripheral vascular resistance HR SA node AV node Contractility

Peripheral vascular resistance: decrease X2 HR: decrease SA node: decrease AV node: decrease X2 Contractility: decrease X2

Nifedipine: Peripheral vascular resistance HR SA node AV node Contractility

Peripheral vascular resistance: decrease X3 HR: increase SA node: -- AV node: -- Contractility: --

Angiotensin-Converting Enzyme (ACE) Inhibitor: Captopril, Lisinopril, (other "-prils"): Adverse effects

Persistent cough (thought to be due to increased bradykinin levels), hypotension, hyperkalemia, angioedema (potentially fatal), fetal pathologies, reduction in GFR

Vasodilator: Nitroprusside: problems

Postural hypotension and subsequent tachycardia (baroreceptor reflex), headache, cyanide toxicity Methemoglobinemia due to accumulation of nitrite ions complexing with hemoglobin forming methemoglobin (lower affinity for oxygen)

A patient presents in the emergency department with acute hypotension that requires treatment. Hypovolemia is ruled out as a cause or contributor and information gathered from the patient and family indicates the cause is overdose of an antihypertensive drug. Part of the usual approach to managing acute hypotension not caused by hypovolemia is to infuse a pharmacologic (ordinarily effective) dose of phenylephrine, an α-adrenergic agonist with no α-antagonist or β-blocking activity. You follow that course and your patient's blood pressure fails to rise. A second dose doesn't work either. On which antihypertensive drug did the patient most likely overdose?

Prazosin

A patient presents with what was initially thought to be Stage 2 hypertension. The actual underlying cause—a pheochromocytoma—is not looked for nor detected in the initial work-up. An oral antihypertensive drug is prescribed. We soon find that the patient's blood pressure has risen to levels above pretreatment levels—so much so that we are worried about imminently dangerous effects from the drug-induced worsening of hypertension. Concomitant with the drug-induced rise of blood pressure the patient develops signs and symptoms of heart failure. Which of the following drugs was most likely administered?

Propranolol

Beta Adrenergic Antagonists ("Beta Blockers"): Propranolol, Metoprolol, Esmolol: Action

Propranolol: Nonselective b1 and b2 antagonism Metoprolol, Atenolol, Esmolol: Selective b1 antagonism (preferred for HTN over propranolol) Effect: decrease heart rate and contractility, decrease renin release No effect on blood pressure in normotensive patients

What effect will inhibition of beta1 receptors in myocytes have on intracellular calcium?

Reduction of calcium entry into myocardial cells due to phosphorylation of membrane calcium channels Results in decreased heart rate and decreased myocardial contractility

Direct Vasodilator: Hydralazine: Problems

Reflex sympathetic activation resulting in tachycardia (may provoke angina or ischemic arrhythmia) and renin release (prevent by combining with beta blocker) Others: headache, edema (prevent by combining with loop diuretic) Lupus-like syndromes

Vasodilators mechanisms

Release of NO from drug or endothelium Reduction of calcium influx Hyperpolarization of smooth muscle membrane through opening of potassium channels Activation of dopamine receptors

Direct Vasodilator: Hydralazine: Clinical use

Secondary treatment for hypertension, hypertensive emergencies, heart failure (particularly in combination with isosorbide dinitrate in African Americans)

Vasodilator: Nitroprusside: clinical use

Short-acting (iv onset <1 min): used for hypertensive crisis, severe heart failure

Beta Adrenergic Mixed Antagonists: Labetolol, Carvedilol: problems

Similar to traditional beta blockers

A 69-year-old male presents with symptoms of thirst and dizziness, and physical evidence of orthostatic hypotension and tachycardia, decreased skin turgor, dry mucous membranes, reduced axillary sweating, and reduced jugular venous pressure. He was recently placed on an angiotensin-converting enzyme inhibitor for his hypertension. Urinalysis reveals a reduction in the fractional excretion of sodium and the presence of acellular hyaline casts. The internist suspects acute renal failure of prerenal origin, which has increased renin secretion by the kidney. A stimulus for increasing renal renin secretion is an increase in which of the following?

Sympathetic nerve activity

Vasodilators compensatory response

Tachycardia, activation of RAAS

Hypertension Treatment Strategies: Monotherapy

Thiazide, CCB (usually dihydropyridine), or ACE-I or ARB Monotherapy can normalize blood pressure in 30-50% of patients with mild hypertension If patient is unresponsive to initial drug after 4-6 weeks, there is 50% chance of being normotensive switching to a second drug class and 60-80% for third drug class as monotherapy Increasing dose provides small increases in therapeutic effect but substantial increases in toxicity As disease progresses additional drugs are needed to control blood pressure

Consequences of "Beta Blocker Withdrawal Syndrome"

We conducted a population-based, case-control study of risk factors for first events of coronary heart disease in patients with high blood pressure. All subjects had hypertension treated with medication. The 248 cases presented with new coronary heart disease from 1982 through 1984, and the 737 controls were a probability sample of health maintenance organization patients free of coronary heart disease. The health maintenance organization's computerized pharmacy database identified recent stoppers--patients who did not fill their prescriptions regularly enough to be at least 80% compliant. After adjustment for potential confounding factors, subjects who had recently stopped using beta-blockers had a transient fourfold increase in the relative risk of coronary heart disease (relative risk, 4.5; 95% confidence interval, 1.1 to 18.5). The association was specific to beta-blockers but not diuretics. A withdrawal syndrome immediately following the cessation of beta-blocker use may be an acute precipitant of angina and myocardial infarction in hypertensive patients who have no prior history of coronary heart disease." Solution: Taper the dose when discontinuing!

Angiotensin II AT1 Receptor Blockers (ARBs): Losartan, Valsartan, (other "-sartans"): Particularly useful in patients

With diabetes (compared to thiazides) With ischemic heart disease (compared to direct vasodilators) Patients with chronic kidney disease (diminish proteinuria and stabilize renal function)

Angiotensin-Converting Enzyme (ACE) Inhibitor: Captopril, Lisinopril, (other "-prils"): Particularly useful in patients

With diabetes (compared to thiazides) With ischemic heart disease (compared to direct vasodilators) Patients with chronic kidney disease (diminish proteinuria and stabilize renal function) Younger white patients (<50) compared with CCBs and thiazides

Beta Adrenergic Mixed Antagonists: Labetolol, Carvedilol: action

a1 antagonism and nonselective b1 and b2 antagonism Labetolol: a1 antagonism and nonselective b1 and b2 antagonism (3:1 b:a) Carvediliol: a1 antagonism and nonselective b1 and b2 antagonism (1:10 a:b) Effect: decrease total peripheral resistance via decreasing a-mediated vasoconstriction resulting in lower blood pressure; prevent reflex tachycardia

Terazosin: Action

a1 antagonism in arterioles and venules Effect: decrease total peripheral resistance with less reflex tachycardia than nonselective antagonist (phentolamine) Compensatory Effects: reflex tachycardia, renin release (co-administer diuretic to decrease retention of salt and water)

Calcium Channel Blockers (CCBs) Verapamil, Diltiazem, Amlodipine: Action

block voltage-dependent L-type calcium channels leading to relaxation of vascular smooth muscle and decrease in peripheral vascular resistance

Non-dihydropyridines: Verapamil & Diltiazem: problems

cardiac depression which may include bradycardia, AV block, cardiac arrest, heart failure; constipation, headache

Clonidine, Methyldopa: Action

central a2 agonist reducing sympathetic outflow from vasomotor centers of brainstem Clonidine: a2 agonism reducing sympathetic outflow from vasomotor centers of brainstem Methyldopa: "false" transmitter: displaces NE from vesicle, converted to a-methylNE which is a2 agonist Effect: decrease total peripheral resistance, decrease heart rate (more consistent with clonidine), reduce renin activity

Terazosin: Mechanism of action

decrease TPR via a1 antagonism -> activate baroreceptor reflex -> increase NE release into myocardium -> increase heart rate via b1 receptors -> negative feedback via a2 receptors in myocardium mitigates NE release

Cardiovascular risk reduction depends on

depends on the degree of blood pressure reduction and is not dependent on a particular drug class Treatment of hypertension is of unquestioned benefit; non-treatment is of unquestioned harm

Direct Vasodilator: Hydralazine: Action

dilation of arterioles (more than veins) by unclear mechanism Mechanism not entirely clear but seems to involve - Reduction in calcium concentrations - Increase in NO synthesis in endothelium - Antioxident effects Reduces blood pressure and afterload

Thiazide Diuretics (Hydrochlorothiazide) Action

diuretic blocking the sodium-chloride symporter (NCC) on the distal convoluted tubule Initially: related to diuretic effect (reduce blood volume and cardiac output) but volume and cardiac output return to normal after about 6 weeks (while anti-hypertensive effects continue) due to compensatory effects ("diuretic breaking") Long-term thiazides lower peripheral vascular resistance (mechanism not clear but may influence contractility of vascular smooth muscle)

Drugs that activate dopamine receptors

fenoldopam

Dihydropyridines: Amlodipine, Nifedipine: Clinical use

first-line hypertension, stable angina (but beware of reflex tachycardia)

Dihydropyridines: Amlodipine, Nifedipine: Problems

headache, peripheral edema

Dihydropyridines: Amlodipine, Nifedipine: Note

little or no cardiac depression

Drugs that cause hyperpolarization of smooth muscle membrane through opening of potassium channels

minoxidil, diazoxide

Non-dihydropyridines: Verapamil & Diltiazem: note

peripheral edema less common than with dihydropyridines

Dihydropyridines: Amlodipine, Nifedipine: Action

potent vasodilators with little effect on heart

Non-dihydropyridines: Verapamil & Diltiazem: clinical use

stable angina, arrhythmia

Black patients and older adults (>60) respond better to

thiazides or CCBs But ACE-I or ARBs with specific indications (such as heart failure, prior MI, proteinuric chronic kidney disease)

Drugs that reduce calcium influx

verapamil, diltiazem, nifedipine

Hypertension end mechanism

↑ TPR ; Vascular Disease


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