327 Exam 1 Pharmacotherapy of HTN

Goals of Hypertension

Reduce CVS and overall morbidity and mortality. Use of non-pharmacologic and pharmacologic therapy that has been demonstrated in large-scale clinical trials to reduce the long-term morbidity and mortality associated with hypertension. Address, Incorporate, Prevent, Simplify, Promote, Maintain and Improve

Difference between clinical BP and Ambulatory BP

Both cause mortality and CV mortality but masked HTN is more strongly associated with all-cause mortality than sustained HTN

Risk Based Thresholds for Initiation of BP Treatment in Adults

General Lifestyle Modifications

Weight reduction, DASH diet, decrease dietary sodium, increase physical activity, stress reduction, and moderate alcohol consumption

DASH Diet

Dietary Approaches to Stop Hypertension: 8-10 Servings a day of fruits and vegetables, 2-3 servings of low far dairy products, a diet which is low in saturated fats and cholesterol, increase potassium to 4.7 grams per day

Potassium-based salt

Recommended for patients w/ and w/o HTN. Contraindicated in patients with CKD and on meds that reduce potassium secretion (ACEI, ARBs, Potassium-sparring diuretics)

Exercise Recommendations

3-4 Sessions per week, on average lasting 40 minutes per session with moderate to vigorous intensity. Or exercising 160 minutes per week of moderate to vigorous exercise

Glutamic Acid

Vegetable protein, Inverse relationship to lowering BP, animal proteins may increase BP

Red and Blue berries

Contain antioxidants known to help lower blood pressure

Napping and Hypertension

Midday naps had a noticeable drop in BP. On average 5mm Hg drop in blood pressure 

Dietary factors of unknown or controversial benefit

fish oil, fiber, calcium, magnesium, carbohydrate, saturated fats, omega-6 polyunsaturated fats, monounsaturated fats

Strategies to Dosing Antihypertensive Medications

Start one drug, titrate to max dose and then add a second drug

Start one drug and then add a second drug before achieving max of the initial

Begin with 2 drugs at the same time, either as 2 separate pills or a single pill combination especially if Stage 2 hypertension

Risk Estimation of BP Treatment Threshold 

Does the patient have an average BP >140/90

Does the patient have existing CVD

Does the patient have diabetes or CKD or is the patient’s short-term risk of CVD

Is the SBP >130mm Hg or DBP >80 mmHg after 3-6 months of lifestyle interventions

PREVENT Risk Score

Ages 30-79, Uses more recent data, used additional risk factors, 10-30 year risk estimates, tends to be lower than ASCVD risk score, most likely more accurate but less used

ASCVD Risk Score

Ages 40-79, used data from 1960-1990, traditional risk factors such as age, sex, BP, cholesterol, 10 year risk estimates

Goal BP

<130/80

Initial Monotherapy

Initiation with 2 first line agents of different classes, either as separate agents or in a fixed dose combination is recommended with stage 2 HTN an average BP of >20/10 the fixed target

First-line HTN Medications

Thiazide diuretics, Calcium Channel blockers, ACE inhibitors, ARBs

Examples of Thiazide Diuretics

HCTZ, chlorthalidone, indapamide, metolazone

Examples of Loop diuretics

Furosemide, bumetanide, torsemide

Examples of Potassium sparing diuretics

Triamterene, amiloride

Examples of Aldosterone Antagonists

Spironolactone, eplerenone

Thiazide Diuretics

Preferred over loop when CrCl >30 ml/min, they are all equally effective, and have ancillary benefits (reduced CV events, lower HF)

Side Effects of thiazide diuretics

Hypokalemia, hyperglycemia, hyperlipidemia, hyperuricemia, polyuria, and photosensitivity (sulfonamide)

Loop Diuretics

Not directly used for HTN, preferred for people whose CrCl <30 ml/min

Side effects of loop diuretics

Similar to thiazide, usually dose related, hypocalcemia (blocks Na and Ca reabsorption)

Potassium sparing diuretics 

Help prevent the loss of potassium and magnesium that normally occur with thiazide or loop diuretics. They are weak antihypertensives but are additive in effect in combination with a thiazide or loop. Many drug interactions.

Side effects of potassium sparing diuretics

Hyperkalemia

Aldosterone Antagonists

Additive hypotensive effects when used in combination with thiazide or loop agent. Inspira is indicated for mono or combination therapy for hypertension

Spironolactone Dosing and Side effects

Min 25mg, max 400 mg, usually 25-50 mg max 2x/day. May decrease mortality in HF, associated with gynecomastia

Eplerenone (Inspra)

Min 25mg, usually 50mg up to 2x/day. Four weeks for full effect. Selective Aldosterone Receptor Antagonist. Broad range of interactions are likely.

What is eplerenone cleared through

CYP3A4 isozymes

Eplerenone (Inspra) Adverse effects

HA/Dizziness/GCT elevations, little evidence of gynecomastia, breast tenderness, menstrual irregularities. Avoid use if CrCl <50ml/min

ACE inhibitors

All are equally effective, differ in duration and tissue penetration, drug interactions are similar, can slow progression of HF, they are beneficial post MI, and they slow the progression of diabetic nephropathy.

ACEI side effects

Avoid in pregnancy due to teratogenicity, acute renal failure and death in neonates; Renal insufficiency, hyperkalemia. Hypotension (common in Na or volume depleted individuals), Cough, rash, RF (stop or reduce dose  if CrCl inc. 35%), angioedema

Angioedema

Can occur in the face, larynx, and GI tract. Facial, airway, and tongue swelling. Can occur due to cross reactivity with other ACEI and ARBs

What is a major risk factor for the development of hyperkalemia with ACEIs?

Presence of renal dysfunction

Angiotensin II Receptor Blockers (ARBs)

Flat-dose response relationship. Monitor renal function while in use. Slight favor to ARBs over ACEI

Side effects of ARBs

Avoid in pregnancy (teratogenicity, acute renal failure in neonates), orthostatic hypotension, renal insufficiency, hyperkalemia, angioedema (less likely than ACEI), cross reactivity with ACEIs

ARB Monitoring

Monitor hyperkalemia: baseline is 102 weeks after initial dose or changes made. Monitor blood pressure lowering affects

Why should ACE inhibitors and ARBs not be used together

Combining them does not improve health outcomes but instead increases the risk of serious side effects like hyperkalemia and renal failure 

Direct Renin Inhibitor

Newer class of antihypertensive. Drug is poorly absorbed, and high fat meals further reduce absorption. Available in 150mg or 300mg tablets, dose changes not necessary for renal or hepatic impairment. Generic name is Aliskiren and brand name is Tekturna.

Indication for Aliskiren

Treatment of HTN as monotherapy or in combination. Caution: angioedema and severe hypotension has been reported

Side effects of Aliskiren

Dose related GI effects, Rash, elevated uric acid levels, renal stone, single episode tonic-clonic seizures. <1% reported nasopharyngitis, dizziness, fatigue, upper respiratory infection, back pain, cough

Calcium Channel Blockers

All equally effective but use dihydropyridines over non-dihydropyridines. Differ in pharmacodynamic properties. Decreases risk of stroke but not as strongly as ARBs, no benefit to HF or CHD.

Examples of dihydropyridine

Amlodipine, felodipine, nifedipine

Examples of non-dihydropyridine CCB

Diltiazem, Verapamil

Dihydropyridine side effects

Reflex tachycardia, dizziness, flushing, headache, peripheral edema, drowsiness

Non-dihydropyridine side effects

Bradycardia, affects AV conduction, contraindicated in patients with AV block, dizziness, flushing, headache, peripheral edema

General Calcium Channel Blocker Side effect

Lower extremity edema (which is why it is not used in HF pts.), constipation, gingival hyperplasia

Important Counseling Points for CCBs

Report weight gain and peripheral edema to prescriber. May use stool softener if constipation occurs

Diltiazem Dosing

Usual: 180-240mg

Min-Max: 120-540mg

Once daily

Verapamil Dosing

Usual: 180-240mg

Min-max: 120-540 

Once daily

ARB compared to CCB

ARB resulted in a 3-5% absolute lower rate of new onset diabetes than CCB. No difference in overall mortality. `

Beta Blockers

All BBs are equally effective in HTN. Useful post MI decreases both morbidity and mortality in HF pts. Lower HR but that may cause more MIs and increase CV deaths. Some are cardio selective and are safer in patients with asthma, PVD, and DM

Cardio selective BBs

Metoprolol, atenolol, bisoprolol. Cardioselectivity is dose related and variable

Non-cardioselective BBs

Propranolol, timolol

Side effects of Beta Blockers

Hypotension, bradycardia, fluid retention, fatigue

Contraindicated in pts with HR < 60 and SBP <100 mmHg

Proceed with caution in pts. with asthma/COPD

Increases triglycerides and decreases HDL-C

Weight Gain

Decreases exercise endurance 

Little effect on LVH regression

BB Counseling

Monitor HR and BP. Use caution with positional changes, especially with initiation of medication. Initial fatigue may occur but may occur with time and steady state levels of medication. Do not stop abruptly taper over 10-14 days, can cause unstable angina, MI, or death.

Intrinsic Sympathomimetic Activity

No one uses these. But in theory it is better for patients with sinus bradycardia and PVD. Examples: pindolol, penbutolol, carteolol, acebutolol. Have alpha blocking activity as well as membrane stabilizing action.

Nebivolol

Brand name is Bystolic. It is a Beta-1 selective agent with nitric oxide vasodilating properties. Can cause HA, dizziness, diarrhea, and fatigue. It maintains systemic flow and blood flow to target organs; it lowers vascular resistance and supposedly have very little metabolic adverse effects. Comes in 2.5, 5, and 10mg doses

Losartan Intervention for Endpoint (LIFE) reduction study

Primary composite outcome with losartan, lower risk of fatal and nonfatal strokes, slightly lower risk of CVD, similar risk of myocardial infarction

Selective Alpha-1 Blocker

Should not be used strictly for hypertension, they lower BP but have a lot of potential side effects and inferior CV outcomes. Use cautiously in elders. Have adverse effects on morbidity and mortality. Add multiple drugs and it will increase the risk of HF.

Ancillary benefits of Alpha-1 Blockers

Benefit for benign prostatic hypertrophy. Also used for off label conditions such as PTSD, nightmare, Raynaud’s. It is lipid and glucose neutral.

Side effects of Selective Alpha 1-blockers

First dose hypotension, dizziness, palpitations, and possible syncope with changing positions. Usually happen with first dose and increased dose.

Alpha-1 Blockers Counseling points

Tell pts. to take at bedtime, orthostatic hypotension

Zilebersian

Is an RNA interference agent that inhibits hepatic angiotensin synthesis. In pts. with 200mg dose BP decreased 10/5 mmHg. Results were similar with high salt diets and with irbesartan. Side effects: Headache and injection site reaction 

Obj of Medication in Research

To determine whether treatment with a CCB and/or an ACEI lowers the incidence of CHD or other CVD events vs treatment with a diuretic

Why is research in medicine so important

Very large population of people have HTN, must check for irregularities across the board. Looks to maximize safety across all pops. Can show that changes in recommended doses need to be made.

Main Outcome Measures

Primary outcome was fatal CHD or nonfatal MI. Secondary: mortality, stroke, combined CHD (Coronary revascularization procedures, angina, and hospitalization), combined CVD (stroke, angina, heart failure, and PAD)

ALLHAT Summary

No difference between chlorthalidone, amlodipine, and lisinopril in primary outcome and all-cause mortality. Amlodipine has a higher than of HF than chlorthalidone, and lisinopril vs chlorthalidone found a higher rate of HF, stroke, and combined CVD with lisinopril

SPRINT Trial

Tested whether a treatment strategy aimed at reducing systolic BP to <120 or <140 will reduce the occurrence of cardio-vascular disease. Found that CVD rates will be lower in the interventive intervention arm.

Central alpha-2 agonists

Clonidine, guanabenz, guanfacine, methyldopa. Can cause rebound hypertension.

Direct Vasodilators

Hydralazine and Minoxidil

Clonidine

.1, .2, and .3mg tablets or transdermal patch. Gradually DC over 1 week for oral therapy. Do not use in the elderly. Abrupt stop can cause rebound hypertension. 

Combined Antihypertensive Therapy

For aggressive BP goals. Monitor effectiveness with added drugs.

Treating stable Ischemic Heart Disease

Target BP <130/80. First line meds: BBs, ACEIs/ARBs for pts. with previous MI or stable angina. Follow up with dihydropyridines, CCBs, mineralocorticoid receptor antagonists

Treating HTN with HF

Target is <130/80. Nondihydropyridines CCBs are not recommended for pts. with HF. Adults with HF and HTN after management of volume overload should be treated with ACE or ARB plus beta blocker plus other medications to goal 

Treating HTN with patients with chronic kidney disease

Pts. with HTN and CKD (stage 3 or higher) treat with ACE inhibitors or ARB. After a kidney transplants treat with CCB to improve GFR and kidney survival

Treating HTN for secondary Stroke prevention

Should include thiazide, ACE, or ARB, or a combo of thiazide + ACE

Patients with Diabetes and Hypertension

Can use all first line: diuretics, Ace Inhibitors, ARBs, CCBs. ACE and ARBs should be considered in the presence of albuminuria 

HTN in Black Adults

Can start thiazide or CCB. Can add ACE and ARB if necessary.

Women with HTN

Oral contraceptives can increase BP. Hormone replacement therapy does not raise BP. Consider other forms of contraception if necessary

Pregnant women with HTN

Use Nifedipine XR and/or labetalol. ACEI, ARBs, and direct renin inhibitors are contraindicated in pregnancy. Also avoid atenolol, nitroprusside, and Potassium sparing Diuretics. Can be counseled for low dose Aspirin to reduce the risk of preeclampsia for high-risk preeclampsia patients. Goal is to reduce <140/90 before 20 weeks gestation.

Urgent BP Control in Pregnancy

SBP is >160 and DBP is >110. Labetalol IV, Hydralazine IV or IM, Nifedipine (immediate release) orally

Elderly and HTN

Thiazide diuretics and long acting CCB. Start with small initial dose. ACEI is good choice if MI, HF, or CKD present. BB only if another condition warrants it. Avoid peripheral alpha blocker or central alpha agonists

Very Elderly and HTN

>80 years old. Lowering BP may delay dementia

Complementary medicine for HTN

Danshen, grape seed extract, cocoa, Astralagus, black tea, blueberry powder, beetroot juice, vitamin D

Resistant Hypertension

BP that remains above goal despite being on 3 different medications, ideally ne medication should be a diuretic. Screening for primary aldosteronism is recommended regardless of whether hypokalemia is present. See if a medication is possibly causing it. Consider renal denervation treatment

Causes of Resistant Hypertension

Poor BP technique, adherence, genetic factors, white coat effect, obesity, alcohol, dietary salt, drug related causes.

Treatment of Resistant Hypertension

Eplerenone and spironolactone are preferred in primary aldosteronism and resistant hypertension. Can be added as fourth agent. Avoid potassium supplements or potassium sparing diuretics in people with severe renal dysfunction. If K-sparring meds cannot be tolerated try BBs, ABs, or direct vasodilators

Renal Denervation

A procedure that disrupts the renal sympathetic nerves via ablation. Goal is to reduce sympathetic activity and reduce blood pressure. Considered for patients with true resistant hypertension after excluding a secondary cause, optimizing medical therapy, and confirming adherence.

Promoting Adherence

Build patient trust, increase motivation. Consider beliefs and attitudes. Both clinician and patient must agree on BP Goals

Strategies to promote adherence

Education, patient and family involvement, regular communication, discussion of progress, link drug administration to daily activities, minimize number of daily doses, use of combo of products, reminder strategies, medication affordability and access

BP Readings at home vs in clinic

Are usually 10/5 mmHg higher in clinic than ambulatory at home

Large cuff on small arm

Falsely low BP

Small Cuff on Big arm

falsely high blood pressure

Pharmacist Roles in CVD Risk Reduction

Collaborative practice agreements - can initiate and modify pharmaceutics

Systems approach - CVD risk reduction is challenging in a busy primary care practice, so technology is helpful

LVH

Left ventricular hypertrophy. Is the thickening of the left ventricular myocardium in response to chronic pressure overload or volume overload

Severe hypertension

>180/120. In emergencies admit to ICU and continue monitoring for organ damage. Reduce by oral or IV meds by no more than 25% in the first hour. Then no less than 160/100 in the next 2-6 hours. Then <130 over the next 24-48 hours