13. Hypertension pathopharmacology

when heart is contracting

when heart is relaxing

normal: <120 / <80

elevated: 120-129 / <80

stage 1: 130-139 / 80-89

stage 2: >140 / > 90

no clear cause

risk factors: old age, obesity, salt-heavy diet, no PA

can improve with lifestyle changes

underlying cause

ex 1: tumor -> aldosterone -> retains water -> increased fluid -> high BP

ex 2: low renal blood flow (I.e. atherosclerosis, vasculitis, aortic dissection) -> renin -> retains water -> high BP

primary: usually none

secondary: associated with underlying cause

emergency: confusion, drowsiness, chest pain, breathlessness

systolic > 180 / diastolic > 120

lifestyle changes: diet, PA, stress reduction

antihypertensive meds

decreased renal salt excretion (shift in pressure-natriuresis relationship)

BP is related to the amount of sodium excreted/not by kidneys

remember sodium <3 water (sodium excreted = water excreted)

more fluid = higher BP

increased activity of SNS: this causes vasoconstriction (less space available for blood)

increased activity of RAAS: increased sodium-fluid retention

dysfunction of natriuretic hormones (opposite of RAAS - promote sodium EXCRETION)

insulin resistance - Hb gets glycosylated, which makes them prickly, which damages blood vessels

decreased dietary Potassium, Magnesium, Calcium: they are required for natriuretic hormone function

genetics

increased sodium intake

seems like it is a consequence rather than risk factor

when you are stressed, your SNS is active

SNS is activated quickly, but the downstream paths are slow to get down

so if you're constantly stressed, your SNS is constantly active, so there is time for the pathways to lead to HTN

increased RAAS system

increased SNS -> vasoconstriction -> this is usually a sign that BP is low

kidneys misinterpret this, responds as if the body actually has a low BP, and releases more renin -> more angiotensin II -> more aldosterone -> more Na+ and water retention

this increases BP -> further vasoconstriction

this would be fine if you were hypotensive, but it's a problem when the decreased renal perfusion is due to another reason

K+, Ca2+, Mg2+,

opposite RAAS effects:

- increase diuresis (production of urine)

- increase vasodilation

- decrease aldosterone

- decrease SNS

pressure-natriuresis shift -> HTN

when the RAAS is overactive (in HTN), our NHs are working fine, but they would need to be overactive to compensate for the RAAS

our body is not able to do that on its own, so we use meds that mimic their action

genetic + environment

dysfunction of SNS, RAAS and NHs

increased peripheral resistance

increased blood volume

therefore HTN

easier to get back to normal values

if sustain HTN for a long time -> vascular remodelling -> complications of chronic HTN

vascular remodelling = smooth muscle hypertrophy (bigger) and hyperplasia (more)

this causes narrowing of vessels -> decreased blood flow to organs -> damage (major organs affected: eyes, heart, brain, kidneys)

damage: retinopathy, heart failure, myocardial ischemia, strokes, aneurysms, oedema, kidney disease, glomerulosclerosis...

Canadian Indigenous

3x risk of T2DM

lower access to healthcare, healthy food, PA facilities

2x more smokers

genetic predisposition to gain weight

risk of HTN + cardiovascular disease is 2x greater

new immigrants have less chronic conditions upon arrival

BUT

westernization of diet + lifestyle deteriorates their health

this is a HTN risk factor

amount of fluid cleared from circulation going into urine

= GF + TS - TR

filtration: 180L/day

reabsorption: active transport

secretion: pumps in PCT

collecting duct (distal tubule, at the end)

proximal convoluted tubule: mannitol (65% NaCl reabsorption - too much we don't use)

thick segment ascending limb of Henle's loop: furosemide (20%)

early distal convoluted tubule - thiazides (10%)

late distal convoluted tubule + collecting duct - spironolactone (1-5%)

Increase clearance of fluid by inhibiting NaCl reabsorption -> keep Na+ in the tubules -> keeps water in the tubules

for every 1% you block, + 1.8L of urine output (that's a lot)

hypovolemia (fluid loss)

acid-base imbalance

electrolyte imbalance

used for diuresis even if GFR is low - very powerful (20%)

indications:

- pulmonary edema

- CHF

- edema or HTN when other diuretics fail

adverse effects:

- hypotension, -natremia, -kalemia: severe water, Na+ and K+ loss

- otoxicity (rare)

- possible teratogen

interactions with Digoxin (elderly ppl!)

- hypokalemia -> increases digoxin toxicity

- combine with K+ sparing diuretics to decrease toxicity

main diuretic used in HTN - 1st line drug (less powerful + easier to adjust)

ineffective when GFR is low (10% not enough)

indications

- HTN

- edema associated to mild-moderate heart failure

adverse effects

- same as loop diuretics but NO otoxicity

same interactions as loop

a hormone (has delayed onset)

aldosterone antagonist: decreases synthesis of Na+ and K+ (Na+ stays in urine and K+ stays in blood as transporters are blocked)

uses -> increases urine output but decreases K+ loss

- not a diuretic itself

1- counter thiazide/furosemide toxicity (prevent hypokalemia)

2- heart failure -> aldosterone block = protective effects

adverse effects

- hyperkalemia

- endocrine irregularities (abnormal menses..)

- interactions w/other K+ sparring drugs (ACE inhibitors/blockers)

triamterene + amiloride action

PROTEINS = fast onset, but weaker

direct Na+/K+ inhibition

ACE inhibitors

ARBs (angiotensin II receptor blockers)

Aldosterone antagonists

DRI

there is also local angiotensin II production - at level of tissues, independent of RAAS system

ACE inhibitors acts on only RAAS pathway, while ARBs is on receptors everywhere

2 enzymes:

ACE: angiotensin I -> angiotensin II

Kinase II: brady kinase -> inactive product

main effect: reduces angiotensin II, which results in

- vasodilation

- decreased blood volume

- decreased cardiac VR

adverse effects:

- potassium retention

- fetal injury

main effect: buildup of bradykinins, which results in

- vasodilation

adverse effects:

- vasodilation

- cough

- angioedema (rare)

almost all PO

captopril = only one with short T1/2

almost all prodrugs -> liver failure = decreased efficacy

all excreted in kidneys -> kidney failure = increased toxicity

HTN

- drug of choice

- decreases HTN related mortality

- initial BP drop drops RAAS angiotensin II

- prolonged BP drop due to local angiotensin II drop

heart failure

- drug of choice

- improvement of Sx + increased survival

- may reverse pathologic hypertrophy

nephropathy

- slows down renal damage

- works via GFP drop

myocardial infarction

- decreased mortality + HF developement

diabetic retinopathy

- prevention/slow onset only in T1DM w/out HTN, nephropathy/retinopathy

CVE prevention

- drop risk of MI, stroke, mortality in HIGH RISK PT ONLY

- high risk = CVE history + another risk factor

1st dose hypotension:

- minimize via small initial dose + monitor

- discontinue diuretics 2-3 days prior

cough:

- 10% of pt -> discontinue if severe

- high risk in elderly, female, asian

fetal injury

- teratogenic during 2nd+3rd trimester

- discontinue asap, monitor fetus if exposed

neutropenia

- educate pt to report sign of infection ASAP

- high risk in renal impaired pt

hyperkalemia

- rare -> educate pt to avoid K+ supplement

acute kidney injuries

- worst when combined w/diuretics + NSAIDs

angioedema

affects 1% of pt

caused by excess bradykinin

early Sx= giant edema of tongue, lips, eyes

Tx = epinephrine injection

discontinue FOREVER

diuretics -> nephrotoxicity

antihypertensive Tx -> additive hypotension

drugs that increase K+ -> hyperkalemia, use only if necessary + monitor

lithium -> lithium accumulates when there is a decline in angiotensin-II -> Li has a narrow therapeutic window, so any variation to Li can lead to severe toxicity -> monitor closely

NSAIDs -> antagonist hypertensive effect + nephrotoxicity -> AVOID

ACE-I = block production

ARB = block action

similar effects -> similar indications

no kinin increase

lower overall risk of angioedema

efficacy < ACE-I -> 2nd choice drug

1. effect on vascular smooth muscles: decreased calcium induced contractions -> induces vasodilations

2. effect on heart muscle -> inhibits Ca++ entry -> decreases HR, conduction velocity, force of contraction

(similar effect to Beta-Blockers - no effect on vascular muscle tho)

initiates muscle contraction

- CCBs have greater affinity for blood vessel smooth muscle + heart muscle Ca++ channels

vascular specific - Nifedipine

- site of action is arterioles and heart

non-specific - Verapamil

- site of action is only arterioles

pretty much all treat HTN

some treat angina (nifedipine, amlodipine, nicardipine)

non-specific treat dysrythmias + angina

direct = vasodilation + decrease SA/AV node conduction + contractility (this causes a BP drop)

indirect = rebound baroreceptor reflex increases SA/AV node conduction + contractility (happens due to BP drop - almost immediately counteracts direct effect)

net = vasodilation -> decreased BP and increased coronary perfusion

kinetics:

- PO or IV

- onset = 30mins / peak = 5 hrs

- extensive hepatic metabolism

adverse effects:

- constipation, headache, edema, exacerbated cardiac dysrhythmias + failures

- elderly: chronic eczematous eruptions

interactions (CAN'T COMBINE W/BETA-BLOCKERS):

- digoxin: additive V block effect

- beta-blocker: additive effects

- grapefruit juice: decreased metabolism

toxicity management:

severe hypotension or AV block/bradycardia

- can do gastric lavage to remove Verapamil

- Ca2+ gluconate counters inotropic + vasodilation (not AV block)

- IV norepinephrine counters hypotension

- atropine helps for conduction block

direct = vasodilation -> decrease BP + increased coronary perfusion

indirect = rebound baroreceptor reflex increases SA/AV node conduction + contractility

- this only happens with immediate release formation

- sustained release much preferred (much safer)

net = vasodilation -> decreased BP and increased HR + contractility

kinetics:

- PO or IV

- IR: onset = seconds / peak = 30 mins

- SR: onset = 20mins / peak = 6hrs

- extensive hepatic metabolism

adverse effects:

- headache, edema

- elderly: chronic eczematous eruptions

- heart effects only in overdose

differences vs Verapamil

- little cardiac effects + no constipation

- reflex tachycardia -> prevent w/beta blocker

remember Nifedipine does NOT act on heart

selective to arterioles -> increase CO + decrease heart workload

selective to veins -> decrease CO + decrease heart workload (because most blood pools in veins and doesn't come back to the heart as much)

hypertension, angina pectoris, heart failure, MI, many others with risk of high BP

hydralazine, minoxidil, nitroprusside

RAAS agents, CCB and others are also vasodilators but they also do other stuff

1. postural/orthostatic hypotension -> falls

2. reflex tachycardia (via baroreceptor reflex -> counter with beta-blockers)

3. blood volume expansion (via RAAS -> counter with diuretics)

natural vasodilator that endothelial cells produce -> this med gives it a boost

promotes relaxation using the cGMP pathway, affects both veins + arterioles

fast onset + minimal postural hypotension

metabolized by liver into cyanide groups

IV infusions -> can adjust to desired BP

indications:

hypertensive emergency (>180/>120 mmHg)

- super high risk of organ damage

- strategic use, rapid drop of BP until oral antihypertensive kick in

adverse effects

- excessive hypotension (due to rapid admin)

- cyanide poisoning (high risk with liver disease)

- thiocyanate toxicity: high risk when admin > 3 days

SDP/DBP below 130/80 mmHg

maintain/improve QoL

lifestyle modifications

antihypertensive drugs

decreased morbidity

increased lifespan

decreased stroke 35-40%

decreased MI 20-25%

decreased HF 50+%

1. assess cause + risk factors

2. Tx of cause if secondary HTN

3. intervene on risk factors

4. perform diagnostic test

tests:

- ECG

- cholesterol + triglycerides

- electrolytes (Ca2+, Na+, K+)

- hemoglobin + hematocrit

- urine analysis (creatinine, glucose, urea)

no, there's different risk levels that determine Tx

lower risk = more conservative Tx, wait longer before starting Tx

there's diff BP thresholds for each risk level

Highest risk:

1. high risk pt

- clinical or sub clinical cardiovascular disease

- chronic kidney disease

- estimated 10 year global CV risk > 15%

- age > 75yrs

2. diabetes

moderate risk:

- multiple CV risk factors + 10 year global CV risk > 15%

low risk:

- no target organ damage or CV risk factors

DASH diet : 8-14 mmHg

increased PA : 4-9 mmHg

moderate alcohol: 2-4 mmHg

weight reduction: 5-20 mmHg / 10 kg

relaxation therapies: 4-5 mmHg

smoking cessation

4700mg K+/day

1000mg Ca/day

2000mg sodium /day MAX : 2-8 mmHg

need to combine them together, one alone is not enough

diuretics

- thiazides

- loop diuretics

- potassium-sparring

sympatholytics

- beta blockers

- alpha blockers

- alpha/beta blockers

- centrally acting alpha agonists

- adrenergic neuron blockers

RAAS suppressants

- ACE-I

- ARBs

- direct renin inhibitor

- aldosterone antagonists

Other

- direct-acting vasodilators

- CCBs

there are several combinations formulations, usually:

thiazide + (beta blocker, ACE-I or ARB)

Clonidine

suppression of sympathetic outflow decreases sympathetic stimulation of heart + blood vessels

Mecamylamine

ganglionic blockade reduces sympathetic stimulation of heart + blood vessels

reserpine

reduced norepinephrine release decreases sympathetic stimulation of heart + blood vessels

metoprolol, propranolol

beta1 blockade decreases HR + contractility

prazosin, terazosin

alpha1 blockade causes vasodilation

hydralazine, nitroprusside, thiazide, CCB, minoxidil

relaxation of smooth muscle causes vasodilation

thiazide diuretics, furosemide, K+ sparring

promotion of diuresis to decrease blood volume

metoprolol

B1 blockade suppresses renin release, resulting in vasodilation secondary to reduced production of angiotensin II AND prevention of aldosterone mediated volume expansion

aliskiren

inhibition of renin suppresses formation of angiotensin II thereby reducing vasoconstriction and aldosterone mediated volume expansion

captopril (ACE-I)

decreases formation of angiotensin II, prevents vasoconstriction and aldosterone mediated volume expansion

ARBs

prevents angiotensin-mediated vasoconstriction and aldosterone mediated volume expansion

spironolactone

promotes excretion of sodium and water, reduces blood volume

the target: <140/90 mmHg

Thiazide/thiazide-like diuretic

- Long-acting (e.g. indapamide and chlorthalidone) preferred over short acting (e.g. hydrochlorothiazide)

ACE-Inhibitors

- Contraindicated in pregnancy dt teratogenicity

ARBs

§  Contraindicated in pregnancy dt teratogenicity

o   Long-Acting CCBs

o   Beta-Blockers

- Not indicated as 1^st line >60 yo. -> dt increased toxicity as people age

o   Single-pill combination

Best are:

·      AEE-I + ARB

·      ARB + CCB

·      ACE-I + ARB + Diuretic

1)    Lifestyle modifications

2)    Add 1^st antihypertensive Rx

3)    Substitute or Addition of 2^nd antihypertensive Rx

4)    Substitute or Addition of 3^rd antihypertensive Rx etc

there is drawing to follow EXACTLY

-       To achieve optimal BP targets:

o   Multiple drugs are required to reach target, especially in pt w/T2DM. 

o   Replace multiple antihypertensive agents with single pill combination therapy. 

o   Single pill combinations or monotherapy should be considered for initial therapy. 

o   Low doses of multiple drugs may be more effective and better tolerated than higher doses of fewer drugs. 

o   Reassess pt with uncontrolled BP at least every 2 mths. 

o   The combination of ACE inhibitors and ARBs should not be used -> effects don’t add up  

o   In pt in whom combination therapy is being considered, an ACE inhibitor plus a long-acting dihydropyridine CCB is preferable to an ACE inhibitor plus a thiazide or thiazide-like diuretic

Suspected Resistant Hypertension 

o   Consider white coat hypertension and non-adherence. 

o   Diuretic therapy should be considered

o   β-Blockers, when used in addition to ACE inhibitors or ARBs, have not been shown to have a clinically important effect on BP. 

o   Monitor creatinine and potassium when combining potassium sparing diuretics, ACE inhibitors and/or ARBs. 

o   Consider referral to a hypertension specialist if BP is not controlled after Tx with 3 meds

1. use drugs from diff classes

- increases efficacy (synergistic)

- decreases necessary dosage (toxicity)

- counter adverse reactions (vasodilator + B1 blocker)

2. start w/low dose

- HTN is not immediate threat

- decrease risk of baroreceptor reflexes/toxicity

3. gradually step-down meds

- after 1 year of good BP control only

- lifestyle modifications can sustain BP regulation w/smaller doses or # of drugs

- monitor BP regularly once discontinuing

inaccurate measurements

suboptimal Tx regimens

- dose too low

- inappropriate combos

poor adherence

- diet, PA

associated conditions

- obesity, tobacco, alcohol

drug interactions

- NSAIDs, oral contraceptives, cocaine, steroids, OTC diet supplements...

secondary HTN

- renal insufficiency

- thyroid disease

- renovascular disease

-       Hyperkalemia → K+-Sparing Diuretics (just makes it worse)

-       Asthma → Beta2-Blockers (exacerbates the Sx)

-       AV Heart Block → CCBs (use a vascular specific CCB and not a non-specific CCB)

-       Diabetes & Renal Disease → Thiazides

African Americans:

- increased HTN incidence + early onset

- monitor + lifestyle = crucial

- diuretics + CCBs = best Rx

- ACE-I + B-blockers efficacy < caucasians

children + teens

- no specifics

- lower dosage

elderly

- increased postural hypotension risk

- use low doses + gradual increase

most common pregnancy complication (10%)

BP should go back to baseline after birth, but 9mths is long enough for complications

chronic HTN: present before week 20

severe HTN (160+/110+) -> treat

moderate HTN -> risk > benefits

AVOID TERATOGENS (RAAS agents)

preeclampsia (PE) : high BP + proteinuria after 20th week

- risk prevention: low dose aspirin or L-arginine before week 16

- late term mild PE: labor induction

- early mild PE : controversial, no evidence

- severe PE : indication = best

if u wait, labetolol to decrease BP, Mg2+ sulfate to decrease epilepsy

lack of adherence to Rx

- chronic, slow progression with no Sx most of development

- difficult to justify use of Rx + prove efficacy

education -> risk, goals

self monitoring -> teach to record + follow BP

minimize side effects -> encourage reporting

collaborative relationship -> involve in choices

simplify Rx -> min # of drugs

other measures -> support network