PHR 946 - Block 1: Hypertension, Diuretics, Antihypertensives

blood pressure

determined by the amount of blood the heart pumps and the resistance to blood flow in the arteries

- ↑ blood from heart = narrowing of lumen of the arteries

hypertension

high blood pressure

- long term force of the blood acting on artery walls

- becomes high enough to produce vascular/ tissue damage

- contributes to heart and vascular disease

- if chronically untreated: contributes to other diseases such as stroke, aneurysm, myocardial infarction, heart failure

HTN numbers

- normal: < 120/80 mmHg

- elevated: systolic 120-129 AND diastolic < 80 mmHg

- stage 1: systolic 130-139 OR diastolic 80-90 mmHg

- stage 2: systolic 140+ OR diastolic 90+

HTN symptoms

- most have no readily observable S&S

> just consistently high BP and mild headache

> many do not know they have high BP

- hypertensive crisis (180+/120+)

> severe headache, confusion, agitation, seizures

> serious and immediately life threatening

RAAS pathway

renin angiotensin (aldosterone) system

- raises BP by vasoconstriction and sodium/ water retention

- low bp / low renal perfusion → kidneys (juxtaglomerular cells) release renin

- renin: angiotensinogen → angiotensin I

- ACE (angiotensin converting enzyme): angiotensin i → angiotensin I

- angiotensin II: vasoconstriction + ↑ aldosterone

- aldosterone: ↑ sodium + water reabsorption → ↑ blood volume

- result: ↑ blood pressure and perfusion

primary HTN

- no identifiable cause

- 90% of cases

- contributing factors: genetic predisposition (diabetes, obesity, dyslipidemia, age, gender) and environmental factors (stress, smoking, obstructive sleep apnea, diet, alcohol)

- 3 types: moderate or high renin HTN, low renin HTN, resistant HTN

3 types of primary HTN

1. moderate or high renin HTN

- most common

- treated with anti-RAS medications (ACEis or ARBs)

2. low renin HTN

- plasma renin activity is 1/10 of high renin HTN

- treated with diuretics or calcium channel blockers

3. resistant HTN

- often requires 3+ medications

contributors to primary HTN

- impaired renal function

> kidneys fail to recognize and compensate for ↑ BP or volume expansion

> chronic kidney disease is prevalent in pre-HTN (GFR <60)

- excessive sympathetic activity

> stimulation of juxtaglomerular apparatus cells → excessive renin secretion

> leads to excessive AngII, aldosterone, and Na+ recovery causing increases in blood and extracellular fluid

> one treatment is ablation of renal efferent/ afferent nerves

secondary HTN

- occurs secondary to another disease

> need to treat underlying disease to control the HTN

- causes: renal or vascular disease, aldosterone dysfunction, Cushing's, pheochromocytoma, thyroid disease, some medications (steroids, amphetamines, MAOIs)

genetic component of HTN

- expression of mutants of a serine/ threonine kinase is associated with elevated BP

> results in elevated expression of the kinase, increasing BP in both hetero and homozygotes

- the kinase phosphorylates Na/K/2Cl transporter in the thick ascending loop of Henle (where loop diuretics target) AND Na/Cl transporter in the distal tubule (thiazide sensitive)

> both are activated, enhancing Na uptake out of the urine and increasing BP

- 20% with european ancestors carry a copy of the mutant gene

sites of action of diuretics in the nephron

carbonic anhydrase inhibitors

- proximal tubule

- ↓ H⁺ secretion → ↓ Na⁺ reabsorption → ↑ urine output

loop diuretics

- thick ascending limb of loop of henle

- inhibit Na⁺-K⁺-2Cl⁻ co-transporter

thiazide diuretics

- distal convoluted tubule

- inhibit Na⁺-Cl⁻ co-transporter

K⁺-sparing diuretics

- collecting duct

- block aldosterone or enaC → prevent K⁺ loss

thiazide diuretics

hydrochlorothiazide (HCTZ), chlorothiazide, indapamide, chlorthalidone

- developed from carbonic anhydrase inhibitors

- MOA: blocks the Na/Cl transporter in the distal convoluted tubule

> lowers BP 15-20 mmHg

- used for HTN (often 1st line!) and edema

- benefits: well tolerated, safe, inexpensive, reduces blood volume and ECF volume

- other effects: reduction in serum K+ (avoid in arrhythmias), reduced Ca++ excretion (avoid in hyperCa), reduced uric acid excretion (avoid in gout)

- ADE: hypoK+, hyperlipidemia, hyperuricemia, hyperglycemia (diabetes), hypersensitivity risk in sulfonamide allergies

thiazide PK

- most well absorbed

- onset within 2 hours (oral)

- dosage depends on potency

> chlorothiazide is oldest and least potent

- t1/2 is from 2 hours - 2 days

- most are renally cleared

juxtaglomerular apparatus

- a group of cells located between the afferent and efferent arterioles, and the distal tubule in the nephron

- regulates: glomerular blood flow and filtrate rate, renin release

- low levels of filtrate / decreased NaCl delivery in the distal convoluted tubule causes macula densa cells to send signals to the JG cells to stimulates release of renin & decrease release of adenosine (a a vasoconstrictor) that acts on the afferent arteriole

renin angiotensin system (RAS)

- renin is released into the blood by JG cells

> cleaves Ang to Ang I

- angiotensin converting enzyme (ACE) forms Ang II

> ACE is expressed in endothelial cells

> Ang II conserves Na+ and raises blood pressure

angiotensin

a peptide hormone that constricts blood vessels, causes the retention of sodium and water, and produces thirst and a salt appetite

- continually released from the liver

- renin cleaves Ang into 10 amino acids residues to form Ang (rate limiting step)

- once Ang I is formed, it is rapidly converted to Ang II

- Ang plasma levels increase by: corticosteroids, thyroid hormone, and inflammation

angiotensin II

a potent vasoconstrictor that raises BP

- increases aldosterone synthesis and secretion

- stimulates ADH release

- promotes Na+ reabsorption in the proximal tubule

- stimulates thirst center in hypothalamus

pharmacological targets in the renin-angiotensin pathway

renin

- conversion of Ang to Ang I

> released from kidney JG cells

> inhibitor: aliskiren (Tekturna)

angiotensin converting enzyme (ACE)

- cleaves Ang I to Ang II

> inhibitors: captopril, enalpril (Vasotec), fosinopril, lisinopril (Zestril), rampril

AT1 (Ang II receptor)

- most closely associated with hypertension

> inhibitors: losartan (Cozaar), candesartan (Atacand), valsartan (Diovan)

aliskiren

Tekturna

renin inhibitor antihypertensive

- MOA: direct renin inhibitor

> binds directly to catalytic site of renin and inhibits metabolic activity converting Ang to Ang I

- reduces plasma renin activity by ~60%

- lowers BP by ~10-15

- not recommended over ACEis or ARBs

- ADE: hyperkalemia, hypotension, fetal toxicity

- PK: poorly absorbed (take without food), t1/2 = 24 hrs

angiotensin converting enzyme (ACE)

converts Ang I to Ang II

- also degrades bradykinin (a vasodilator and airway smooth muscle constrictor)

- primarily located on luminal surface of endothelial cells in numerous tissues

- inhibition: decreases Ang II levels, increases bradykinin levels, increases vasodilation

ACE inhibitors

angiotensin converting enzyme inhibitors

captopril, enalapril, lisinopril (-pril)

- MOA: decreases conversion of Ang I to Ang II

> peripheral arteriolar vasodilation and increased large artery compliance

> also reduces aldosterone secretion

- often used for monotherapy, or can be combined with a diuretic or other antiHTN

- ADE: hypotension (start w lower dose), persistent dry cough, angioedema, fetal toxicity, hyperkalemia, reduced renal function/ acute renal failure

- additional indications: heart failure, myocardial infarction w left ventricle dysfunction

angiotensin II receptors

2 types: AT1 and AT2

- both are G-protein coupled receptors (GPCR)

AT1:

- mediate most known effects of Ang II

> vasoconstriction, release of ADH, secretion of aldosterone

AT2:

- mediate vasodilation

angiotensin II receptor blockers (ARBs)

losartan, candesartan, valsartan (-sartan)

- MOA: antagonize Ang II receptors (AT1 with high affinity)

> essentially irreversible

- ADE: (lower than ACEis) cough, angioedema, detal toxicity, hyperkalemia

- additional indications: heart failure, CKD, post myocardial infarction

ACEis vs ARBs

- ARBs reduce activation of AT1 receptors more effectively than ACEis

- ARBs permit activation of AT2 receptors (these receptors mediate vasodilatory effects)

- ACEis increase bradykinin levels (a potentially beneficial vasodilator, but has ADE)

- both decrease systolic BP similarly ~10 mmHg

- both are less effective in low-renin HTN

aldosterone

principal mineralocorticoid

- promotes recovery of Na in the late distal tubule and collecting duct

> Na retention = promotes water reabsorption

> promotes K loss in exchange for Na

- synthesized in: adrenal cortex (outermost)

- released in response to: Ang II, hypoNa, hyperK

aldosterone antagonists

spironolactone (Aldactone), eplerenone (Inspra)

- MOA: competitive antagonists of aldosterone at the mineralocorticoid receptor

- used for: HTN unresponsive to other therapies

- ADE: hyperK; activates progesterone and estrogen receptors (spiro only)

- DDI (eplerenone): CYP3A4 inhibitors

- eplerenone has greater specificity for the MR

mineralocorticoid receptor (MR)

- MR is a member of the cytosolic steroid/ vit D/ thyroid receptor subfamily

- located in epithelial cells in the late distal tubule and collecting duct

- aldosterone binds to the MR receptor

- leads to increased expression and activity of the epithelial Na channel, increased Na entry into cells, and increased Na recovery into bloodstream

- increased K secretion occurs secondarily

limitations of aldosterone antagonists

- diuretic effectiveness depends on Na delivery to distal tubule and collecting duct

> normally a small amount (2%) of Na reaches this area

> aldosterone antagonists are most effective in combo with other diuretics that help more Na get to this point

- aldosterone antagonists aren't effective in the absence of circulating aldosterone

> diuretic effect = aldosterone levels

hyperkalemia with aldosterone antagonists

- monitor serum K prior to and during therapy

> renal insufficiency increases risk

- may increase hyperK effect of ACEis or ARBs

- K supplements are contraindicated

- avoid combo with other K sparing diuretics

amiloride

another less common K sparing diuretic

- MOA: inhibitor of epithelial Na channels

- [black box]: hyperkalemia

complications of uncontrolled HTN

- increased risk of heart disease and stroke

> leading causes of death in US

- effects on other organ systems (eyes, kidneys, peripheral vasculature)

causes of HTN

1. primary (essential)

- 90% of cases

- likely genetics and environmental factors

2. secondary

- obstructive sleep apnea

- SKD

- drug/ alcohol induced

- thyroid disorders

- primary aldosteronism

dietary factors: high Na, low K, low Ca, low Mg, low fruits/ veggies/ fiber, alcohol, caffeine

nondietary factors: genetics, obesity, low physical activity, obstructive sleep apnea, psychosocial stressors, air pollution

drugs/ substances that may raise BP

OTC

- alcohol

- caffeine

- decongestants (pseudoephedrine, phenylephrine)

- herbal (St Johns Wort)

- black licorice

- recreational drugs (cocaine, bath salts)

Rx

- sudden withdrawal of central-acting sympatholytics (clonidine, tizanidine)

- amphetamines

- antidepressants (MAOIs, SNRIs, TCAs)

- OCPs

- systemic corticosteroids

taking BP at home

- use an automatic, cuff-style, upper arm (bicep) monitor

> make sure it matches size of arm

> make sure it is a validated cuff

- avoid smoking/ caffeine/ exercise for 30+ minutes before

- empty bladder

- do not talk

- relax with legs uncrossed

- rest arm on table

diagnosing HTN

- normal: < 120/80 mmHg

- elevated: systolic 120-129 AND diastolic < 80 mmHg

- stage 1 HTN: systolic 130-139 OR diastolic 80-90 mmHg

- stage 2 HTN: systolic 140+ OR diastolic 90+

must have an average of 2+ readings taken on 2+ visits

- out of office measurements may help diagnose and guide treatment

baseline lab testing for pts with HTN

- complete metabolic panel (CMP)

- complete blood count (CBC)

- lipid profile

- hemoglobin A1C

- thyroid stimulating hormone (TSH)

- urinalysis

- urine albumin:creatinine ratio (UACR)

- 12-lead ECG

HTN lifestyle modifications

- weight loss: 5-10% of body weight

- healthy diet (DASH, Mediterranean)

- sodium restriction: <1500 mg/day

- adequate potassium: 3.5-5 g/day

- exercise: 150+ mins/week

- limit/abstain from alcohol and caffeine

when to treat HTN with drugs

1. treat stage II HTN ALWAYS (BP >140/90)

- add lifestyle modifications too

- 2 first line agents recommended (combo pill is best)

2. treat stage I HTN (>130/80) if pt has one of the following:

- clinical CVD (CAD, stroke, HF)

- CKD

- diabetes

- prevent-CVD risk of 7.5%+

if pt doesn't have one of the above, it is reasonable to initiate lifestyle modifications alone. start pharm treatment if not at goal after 3-6 months of lifestyle modifications

- 1 first line agent recommended

common first line anti HTN agents

- ACE inhibitors (-prils)

- ARBs (-sartans)

- thiazide-type diuretics (-thiazide, -thalidone)

- dyhydropyridine CCB (-ipines)

choosing a 1st line option

- a single antihypertensive will lower systolic BP by ~8-10 mmHg

choose based on:

- side effect profile

- DDIs

- prior antihypertensive trials

- cost, medication access

- compelling indications*

compelling indications

1. chronic kidney disease (CKD)

- eGFR <60 mL/min or UACR >30: ACEi or ARB

- CKD I or II with no albuminuria: any 1st line agent

2. diabetes

- eGFR <60 mL/min or UACR >30: ACEi or ARB

- most patients: any 1st line agent

3. heart failure (HFrEF)

- beta blockers, ACEi, ARB, ARNI, spironolactone, or isosorbide (some pts) are all favored due to improving morbidity and mortality in heart failure

4. stroke

- thiazide-type diuretic

- ACEi or ARB

blood pressure treatment goal and follow up

<130/80 mmHg for all adults

- encouragement to get SBP <120, esp in high risk CV patients

- exceptions: limited predicted lifespan, pts with symptomatic hypotension, pregnancy

initiate non-pharm agent and antihypertensive agent, then reassess in 1 month

- if BP goal met: reassess in 3-6 months

- if BP goal not met: assess and optimize adherence + consider intensification of therapy

HTN special populations

older adults

- goal is the same for most (<130/80)

- consider individualized/ relaxed goals for those with: limited life expectancy, high frailty, significant comorbidities, difficulty tolerating treatment

- older adults may experience more side effects with intensive therapy

- consider: combo therapy, pill burden, polypharmacy

pregnancy

- goal is <140/90

- any higher is hypertensive disorders of pregnancy

> chronic HTN (before 20 wks), gestational HTN (after 20 wks), preeclampsia

- 1st line: labetalol, nifedipine XR

- 2nd line: methyldopa, HCTZ, hydralazine

- AVOID: ACEi, ARB, MRA

antihypertensives monitoring and considerations

1. ACEis and ARBs

monitoring:

- hypotension

- BMP/ CMP for: hyperK, Scr increase

considerations:

- avoid in pregnancy

- do not use if hx of angioedema

- do not use ACEi and ARB together

- if cough with ACEi, change to ARB

2. thiazide diuretics

monitoring:

- hypotension

- BMP/ CMP for: hypoK, hypoNa, hypoMg, Scr increase

- uric acid increase (in pts with history)

considerations:

- photosensitivity

3. CCBs

monitoring:

- hypotension

- no routine monitoring

considerations:

- may cause dose related lower extremity edema

hypotension

BP <90/60 mmHg

- symptoms (if present): dizziness, lightheaded, nausea, fainting, confusion, blurry vision

- orthostatic hypotension: sustained reduction in SBP of at least 20 mmHg or BP of at least 10 mmHg within 3 minutes of standing

- causes: antihypertensives, diuretics

> important to adjust medication and drink water

intensification of therapy

options:

- titrate 1st med to max dose

- add a 2nd med

- do both

> typically wait to add a 3rd med until on max doses of 2 meds

in the real world:

- optimize adherence

- some providers will want more aggressive therapy than others

> need close follow up and individualized plan

resistant hypertension

BP above goal despite treatment with 3 antiHTN medications (including a diuretic) at max tolerated doses

OR

BP at goal but requiring 4+ medications

- exclude pseudoresistance (white coat syndrome, adherence)

- identify & reverse contributing modifiable life factors (obesity, inactivity, alcohol, salt intake)

- stop/ minimize interfering substances (NSAIDs, decongestants, estrogen, amphetamines)

- screen for secondary HTN causes

managing resistant HTN

1st line: mineralocorticoid receptor antagonist (MRA)

- spironolactone or eplerenone

other options:

- amiloride, beta blockers, alpha blockers, central sympatholytic drugs, dual endothelin receptor antagonists, direct vasodilators

mineralocorticoid receptor antagonists (MRA)

spironolactone (Aldactone) and eplerenone (Inspra)

monitoring:

- hyperK, hypoNa

- BMP / CMP within 1 week to monitor K

> do not initiate if K ≥ 5, d/c if K >5.5

- increased Scr

> avoid in eGFR <30 or Scr >2.5

- gynecomastia and impotence (spiro)

- AVOID in pregnancy

additional antihypertensive options

beta blockers

- carvedilol, labetolol, metoprolol, bisoprolol

- alpha / beta activity

- preperred in pts with bronchospastic airway disease

- ADE: bradycardia, hypotension, fatigue, depression, reflex tachycardia if abrupt d/c

K sparing diuretics

- amiloride, triamterene

- not very effective as monotherapy

- monitor K close

loop diuretics

- bumetanide, furosemide, torsemide

- preferred in symptomatic HF and moderate-severe CKD

direct vasodilators

- hydralazine, minoxidil

- ADE: fluid retention, postural hypotension, angina, reflec tachycardia, drug induced lupus (hydr), hirsutism (minox)

alpha-1 antagonists

- doxazosin, prazosin, terazosin

- 2nd/ 3rd line in BPH

- ADE: orthostatic hypotension

alpha-2 antagonists/ central sympatholytic agents

- clonidine, methyldopa, guanfacine

- last line due to CNS effects

- ADE: rebound HTN, dizziness, dry mouth, constipation

direct renin inhibitor

- aliskiren

- ADE: hyperK

- AVOID in pregnancy; AVOID use with ACEi or ARB

dual endothelin receptor antagonist

- aprocitentan

- ADE: mild-moderate fluid retention

- AVOID in pregnancy

renal denervation

procedure to reduce renal sympathetic nerve activity

- a catheter is inserted into renal arteries and ablated to reduced release of hormones contributing to HTN

- lowers BP by 4-6 mmHg within 2-3 months

- reserved for adults w resistant HTN despite optimal treatment/ those who have intolerable side effects

hypertensive emergency

a situation in which blood pressure is severely elevated and there is evidence of actual or probable target organ damage

- if no target organ damage = severe HTN

target end organ damage:

- hypertensive encephalopathy

- intracranial hemorrhage

- ischmic stroke

- acute pulmonary edema

- cardiac ischemia (MI or unstable angina)

- aortic dissection

- acute renal failure

- eclampsia

concerning symptoms

- visual disturbances

- headache

- confusion

- weakness/ numbness of extremities

- shortness of breath

- edema

- sweating

- chest pain/ pressure

- referred arm or jaw pain

treating hypertensive emergency & severe HTN

hypertensive emergency

- admit to ICU

- use short acting or continuous IV medications

severe HTN

- no indication to send to ED or hospital

- do not need aggressive BP lowering

- intensification of oral regimen in outpatient setting

calcium channel blockers (CCB)

2 types: dihydropyridines (amlodipine, nicardipine, felodipine, nifedipine XL) and non-dihydropyridines (diltiazem, verapamil)

MOA: prevents calcium from exciting cardiac

and vascular smooth muscle, preventing

muscular contraction and promoting relaxation

- only L-type channel is sensitive to CCBs

- most effective in low-renin HTN

L-type voltage gated Ca++ channel

- made up of multiple subunits

- the voltage-sensitive subunit responds to depolarization of the cell, changing the conformation of pore-forming subunit

- dihydropyridines bind isoform expressed in arteries

- non-dihydropyridines bind isoform expressed in cardiac muscle and cardiac conduction cells

CCB pharmacological properties

decreased Ca++ entry into:

- vascular smooth cells (causes relaxation and arteriolar vasodilation)

- cardiac myocytes (decreases contractility of heart muscle and cardiac output)

- cardiac pacemaker cells (causes slowed conduction and decreased HR)

CCB PK

- well absorbed, but bioavailability is reduced by 1st pass

- highly protein bound

- t1/2 ranges from 3-50 hours

- rapidly absorbed CCBs = rapid BP reduction

- longer acting CCBs = slower onset of action

- can combine a dihydropyridine and non-dihydropyridine because they have different sites of actions

CCB ADE

dihydropyridines

- hypotensive effects (dizziness, headache, syncope)

- peripheral edema (lower legs, ankles)

> increases w higher doses

- mycocardial ischemia

non-dihydropyridines

- bradyarrythmias (verapamil)

- acute decompensated heart failure (verapamil)

baroreceptor reflex

the primary reflex pathway for homeostatic control of blood pressure

- may cause reflex tachycardia and increase cardiac output (dihyropyridines, alpha-1 blockers, direct vasodilators)

sympatholytics

alpha-1-blockers (-zosins), beta-blockers (-lols), mixed alpha+beta blockers

- MOA: block adrenergic receptors & reduce sympathetic outflow from the CNS

> act on the central or peripheral nervous system

- not recommended as 1st line therapy for HTN

alpha-1-receptor antagonists

prazosin (Minipress), terazosin (Tezruly), doxazosin (Cardura)

- MOA: block the post-synaptic alpha-1-receptor

(alpha-1 receptors on vascular smooth muscle cause vasoconstriction)

> no effect on alpha-2 (NE) receptors

- not recommended for initial monotherapy, use when pt not well-controlled on other medications

- increased risk of HF compared to TZD

- may be used with other HTN drugs

alpha-1-receptor antagonists pharmacological effects

produces:

- arteriolar vasodilation and venodilation (blocks vasoconstricting alpha-1 receptors)

- postural hypotension (with first dose)

- inhibition of smooth muscle contraction

alpha-1-receptor antagonists PK, ADE, DDI

PK:

- t1/2: 3-20 hours

- dosing: 1x - 3x daily dosing

> start with low dose and titrate to desired BP. must restart titration if interrupted

- elimination: extensive hepatic metabolism

ADE:

- dizziness

- postural hypotension

DDI:

- other anti-HTN drugs: causes excessive fall in BP

beta-receptor antagonists

beta-1 selective: acebutolol, atenolol (Tenormin), betaxolol, metoprolol (Lopressor, Toprol XL), nebivolol (Bystolic)

non-selective: propranolol (Inderal), nadolol, timolol, carvedilol (Coreg), labetalol (Normodyne)

- effectiveness is independent of beta-1 selectivity

- heart has 80% beta-1 receptors and 20% beta-2 receptors

partial agonists with intrinsic sympathomimetic activity (ISA)

- produce less reduction in: heart rate, force of cardiac contraction, cardiac output, blood pressure

- for hypertension, generally avoid these (acebutolol, pindolol, labetalol)

vasodilating beta-blockers

carvedilol (Coreg), labetalol (Normodyne), nebivolol (Bystolic)

carvedilol

- non-selective

- reduces HR and CO, produces vasodilation to lower total peripheral resistance (TPR)

labetalol

- non-selective with ISA

- modest effect on reducing HR and CO

nebivolol

- highest specificity for beta-1 of any blocker

- beta-3 adrenergic receptor antagonist: activates NO synthase in endothelial cells = vasodilation and relaxation of smooth muscle cells

beta-blockers

- bronchoconstriction (only beta-1 selective agents are safe in COPD)

- bradycardia

- HF patients may not tolerate initial drop of cardiac output

- insulin-dependent diabetes (masks sympathetic nervous system accompanying hypoglycemia)

- CNS effects (fatigue, dizziness, depression)

- [black box]: abrupt withdrawals = cardiac ischemic in pts with ischemic heart disease

centrally acting alpha-2 agonists

clonidine (Catapres), guanfacine (Intuniv)

- MOA: decreased BP by reducing sympathetic outflow

> act by presynaptic alpha-2 stimulation to decreased central NT release

ADE: hypotension, bradycardia, withdrawal syndrome w sudden d/c, seddation, lethargy, depression, tachycardia, excessive BP

- generally last line therapy for resistant HTN, has significant CNS adverse effect

methyldopa

centrally-acting alpha-2 agonist

analog of DOPA

- metabolized to alpha-methylnorepinephrone (MNE) which is a selective alpha-2 agonist

> acts in brainstem to reduce sympathetic outflow

- MNE is NOT degraded by monoamine oxidase, allowing it to accumulate more than NE levels

ADE: sedation, depression, inattention, hypotension, bradycardia, syncope

direct vasodilators

hydralazine (Apresoline), minoxidil

- MOA: directly relax arteriole smooth muscle

> does not affect sympathetic NS and does not cause venodilation

- can be used in combination w other anti-HTN drugs

> diuretics, beta blockers

direct vasodilators pharmacological effects

causes:

- reduction in blood pressure caused by arterial vasodilation

> activates neural compensatory reflexes (↑ sympathetic NS = ↑ vasoconstriction, CO, HR, renin release)

> activation of humoral compensatory reflexes (JG cells detect reduced BP and increase renin secretion)

hydralazine

direct vasodilator

- MOA: inhibits calcium release from arterial smooth muscle sarcoplasmic reticulum

> inhibits myosin phosphorylation, actin interaction, and contraction

- used for moderate to severe HTN not controlled by other medications

minoxidil

direct vasodilator

- MOA: activates K+ channel opening to increased outward flow of K+

> reduces intracellular Ca, reduces interaction of actin & myosin to decreased contraction

- used for HTN not controlled with max doses of a diuretic + 2 other anti-HTN agents

- ADE: headache, vertigo, reflex tachycardia, palpitations, fluid retention, pericardial effusion (black box)