Lec 28 - hypertension treatments

factors of physiological control of BP

cardiac output

baroreceptor

blood volume

vascular tone

phases of hypertension

diagnosis is based on consistent elevated BO measurements over time or by 24 hour BP monitoring

primary or essential hypertension

developed over time

family history, obesity, salt intake, age, etc 

secondary hypertension 

occurs quickly and more severely 

cause can be identified 

majority of renal origin 

may be possible to correct the underlying abnormality 

drugs that can increase BP

NSAIDS

combined oral contraceptives

sympathomimetic agents

stimulants

why os treating hypertension important 

most chronic cardiovascular condition in NZ and most people dont know thye have it - usually symptom free 

silent killer - undiognosed can shorten lifespan by 10-20 years 

consequences of high BP

CVD

neurological diseases

renal diseases

types of drug classes to treat hypertension

reduce blood volume - diuretics

produce vasodilation - calcium channel blockers, alpha blockers

mixed effects (RAAS modulators) - vasodilation and decreased blood volume, ACE inhibitors, ARBs

reduce HR and CO - beta blockers, calcium channel blockers

green script

lifestyle changes first

reduce weight, regular daily exercise

salt restriction

quit smoking

reduce alcohol intake

control diabetes, reduce stress, increase sleep

RAAS system 

works synergistically with SNS - beta receptors stimulate renin release 

renin is released and converts angiotensinogen to angiotensin I which is then converted to angiotensin II by ACE 

angiotensin II cauases vasoconstriction by acting directly on blood vessels, increases blood volume by acting on the kidney, causes aldosterone to be released from adrenal glands 

renin

proteolytic enzyme

released from juxtaglomerular cells in response to low blood pressure, low renal blood flow, sodium in distal tubule, increased sympathetic stimulation (B1-R)

angiotensinogen

plasma protein produced in the liver

angiotensin I

inactive

gets converted to the active form angiotensin II via angiotensin converting enzyme

angiotensin converting enzyme

peptidase (removes a dipeptide) 

found primarily in the lungs but also in endothelial cells throughout the body 

angiotensin II 

powerful vasoconstrictor 

promotes Na+ ad fluid retention by nephron 

stimulates release of aldosterine from adrenal cortex - plays a role in blood pressure regulation and Na+ plasma levels 

enhances sympathetic activities 

RAAS modulators

RAAS regulates blood pressure and fluid balance in the body - the system is crucial in responsing to low blood pressure and dehydration, when activated it causes vasoconstriction and sodium retention

renin inhibitors not approved in NZ

ACE inhibitors

Angiotensin receptor blockers

ACE inhibitors

enalapril

compete with angiotensin I for the catalytic binding site on ACE

prevents ACE from converting antiotensin I to II 

downregulates angiotensin II provoked sympathetic activity = decreased angiotensin II mediated adrenaline release 

reduced aldosterone release - decrease in sodium retention, decreased blood volume → blood pressure 

mostly prodrugs - monitor in patients with impaired liver function 

6 available in NZ 

cant be used during pregnancy 

bradykinin

ACE is also responsible for breaking down bradykinin so decreased ACE = increased bradykinin

causes vasodilation - acts through NO pathway

increased vascular permeability - contributes to inflammation and swelling

pain sensitisation - stimulates nociceoptors, pro-inflammatory

smooth muscle contraction - bronchoconstricition

bradykinin and B2 receptors

Gq receptors located on vascular endothelial cells

IP3 and PKC increase calcium via VGCCs and IP3 receptors 

elevated Ca2+ activates eNOS - converts L-arginine to NO 

NO activated guanylate cyclase - increased cGMP, increased PKG activity, vasodilation 

side effects of ACE inhibitors

hypotension - particularly at start

rash

cough - caused by bradykinin accumulation - airway becomes hyperresponsive, increased inflammation 

angioedema - can occur after years, defective degradation of bradykinin 

where are angiotensin II receptors found

many tissues including heart, brain, kidneys, blood vessels, lungs and adrenal cortex

AT1 receptors

primarily responsible blood pressure modulation effects

vasoconstriction, sodium retention, sympathetic activation, proliferation and hypertrophy, fibrosis, apoptosis, inflammation 

AT2 receptors

though to have more complex functions related to cell growth and differentiation

often acting in opposition to AT1 receptors

vasodilation, natriuresis (sodium excretion)

inhibition of cell growth

anti-fibrotic

anti-inflammatory

AT1 receptors - method of action in smooth muscle

Gq receptors located on vascular smooth muscle - causes vasoconstriction

phosphorylation of VGCCs

AT1 receptors - method of action in renal tubule cells

Gq receptors in distal and proximal tubules 

PKC phosphorylates Na+/H+ exchanger (NH3) - increases sodium reabsorption from the tubular lumen 

Na+/K+ATPase on the basolateral membrane - pumps Na+ into the bloodstream, maintaining a gradient 

angiotensin receptor blockers overvoew 

selective competitive antagonists for AT1 receptors 

candesartan 

generally well tolerated - side effects are related to hypotension 

tight receptor binding and sow dissociation - long lasting RAAS suppression and bettwe 24 hour BP control 

ARB vs ACE

both pretty similar - mostly up to prescriber

ARBs similar but generally better tolerated

dont have additional vasodilation effects of bradykinin but also have low risk of cough and no angioedema 

ACE inhibitors also inhibit the beneficial effects of the AT2 receptors 

calcium channel blockers overview

block L-type voltage gated calcium channels

vessel selective - bind to the extracellular domain outside the channel - stabilise in inactive state and more of these in the vasculature so selective against the heart 

potent vasodilator, reduced BP, minimal effect on HR or contraction 

what drug calcium channel blockers

amlodipine

calcium channel blockers in older patients

particularly effective

the main case of hypotension in elderly is large vessel stiffness

doesnt significantly suppress cardiac output or conduction - safer in conduction abnormalities

generally well tolerated - minimal impact on cognitive function, lipids, or electrilytes

side effects of calcium channel blockers

most are dose dependant

hypotension, facial flushing, dizziness and headache

reduced by slow release capsules

cannot be used in angina as drop in pressure causes angina symptoms

additional treatments of hypertension 

alpha-1 blockers to cause vasodilation 

alpha-2 agonists to decrease sympathetic outflow from the brian

beta blockers to decrease heart rate and constractility 

diuretics to decrease blood volume 

all decrease blood pressure