Pharmacology of hypertension Flashcards
What is hypertension
persistently raised arterial blood pressure
140/90
normal blood pressure
120/80
elevated blood rpessure
120-129/ <80
hypertension stage 1
130-139/ 80-89
hypertension stage 2
140+/ 90+
hypertension stage 3
180+/ 120+
What does clinical management depend on
severity and cause
2 typoes pf hypertension cause
essential (>90%)
secondary
essential hypertension
cause is unknown (idiopathic)
no clear causative factor
secondary hypertension
- renal disorders (role of kidneys in regulating long term BV and therefore BP)
- Endocrine: 1* hyperaldosteronism (fluid regulation)
phaeochromocytoma (sympathetic NS)
Cushing’s syndrome (cortisol)
- Drug induced- abuse- e.g., cocaine (SNS)
- iatrogenic e.g., combined oral contraceptive
- pregnancy- pre-eclampsia
exogenous causes of hypertension
smoking
diet
stress
drugs
endogenous (genetic) causes of hypertensino
obesity
ethnicity
metabolic/ hormonal
renal (RAAS)
CNS
arterial
Consequences of hypertension
inc reased risk of cardiovacular disorder
coronary artery disease
stroke
heart failure
peripheral arterial disease
vascualr dementia
chronic kidney failure
pathophysiology mechanisms involved
- Cardiac output
- Peripheral resistance
- Autonomic nervous system
- Endothelium
- Vasoactive peptides
- Renin-angiotensinogen-aldosterone system
lowering ypertension affects health how?
health benefits
ABP=
CO x TPR
ABP = force on walls
CO= flow of blood
TPR= resistance of vessels to flow
force = flow x resistance
to reduce ABP you
decrease either CO or TPR or both
Cardiac output =
stroke volume x HR
stroke volume is directly proportional to
central venous pressure
paheachromocytoma
benign tumour in adrenal gland
increase adrenaline
increase CVP
responsive vasoconstriction
in most eddential hypertension which of CO and TPR is raised
TPR
chronic adaptive response in blood vessels may lead to
irreversible rise in TPR
Role of autonomic NS in hypertension
heart function (CO)
vessel function (TPR)
SR regulation of pressure and flow: baroreceptor reflex and myogenic response
sympatholytic (antag or inhib SNS transmission) drugs lower ABP
Which receptors does adrenaline act upon to cause vessel smooth muscle constriction- vasoconstriction
A2 adrenoreceptor
ANS heart function
B1 receptors-activation by catecholamines increases sinoatrial (SA) nodal, atrioventricular (AV) nodal, and ventricular muscular firing, thus increasing heart rate and contractility. incvreases CO
vessel function- arteriolar tone regulates TPR and venous tone CVP
a1- vasoconstriction
B2- vasodilation
endothelium
- Endothelial cells produce vasoactive agents
- EDRF (endothelium-derived relaxing fibre) = Nitric oxide (NO) -vasodilator
- prostacyclin - vasodilator
andelyl cyclase- increase cGMP- increase PKG sm. muscle relaxation
endothelin- vasoconstrictor
atheroma (plaque) decreases NO production- constrict
vasoactive peptides
bradykinin- vasodilator (ACE inhibs stop bradykin inactivation- keeping dilated)
Natriuretic peptides-direct vasodilators —–NPR1 (receptor) = guanylyl cyclase = increased cGMP = sm muscle relaxation
+ increase sodium and water excretion- secreasing blood volume
ADH= vasoconstrictor, increases BP and H20 reabsorption
natriuretic peptides
ANP-atrial: secreted by atrium
BNP- brain: secreted by ventricles
CNP- C-type
secreted in response to low BP
link between vasodilation and BP
vasodilation
increase venous capacitance
decrease central venous oressure
decreases ventricular preload
decreases CO
Renin-angiotensin-aldosterone system in BP
longer term regulation of BV (ECF) and systemic vascular resistance
RAAS is a target for many important and effective drugs used in hypertension
ABp and renin
decrease in BP→ increase Symp. activity and decrease GFR
a) increase symp- activates B1 receptors on granular cells of JGA- release of renin
b) macula densa cells detect Na+/Cl- in DCT– decrease GFR – decrease NaCl filtered load– release renin– dailtion of AFF and constriction of EFF– less water is lost through filtration– more in vessels
angiotensinogen
plasma protein produced by liver and secreted into blood
the substrate for renin
gtes converted into ang1
angiotensin 1
endogenous peptide
decapeptide cleaved from N-terminal of ang by renin
converted to ang II by ACE. ACE is widely expressed e.g., lung
angiotensin II
octapeptide produced by cleavahe of C terminal dipeptide by ACE
full agonist at AT1 receptor (GCPR) causing the release of aldosterone (mineralocorticoid) from adrenal cortex- increasinf ECF
arteriolar vasoconstrictor
causes ADH release from posterior pituituary
how many ACE enzymes are there
2
ACE 1
ACE 2
ACE 1
widely expressed in endothelium of lungs and kidneys
has 2 catalytic ZN metalloproteinase domains
cleaves AT-1 - AT-2
also cleaves bradykinin, stopping its vasodilatory effects
ACE 2
1 catalytic domain
cleaves ANG-II antagonising it
AT1 (angiotensin II type 1 receptor)
PGCR (Gi and Gq signalling)
activated by anG ii
Causes:
sm. muscle contraction and vasoconstriction
C and SNS stimulation
aldosterone release
ADH release
tubular Na+ reabsorption in the PCT
endothelin release (vasoconstictor)
Aldosterone
steroid (mineralocorticoid)
full agonist at intracellular mineralocorticoid receptors in tubular cells of the DCT
activation causes na+reuptake
mineralocorticoid receptor
nuclear hormone receptor
Expressed in epithelia with high electrical resistance, e.g. distal kidney tubular cells
selectively changes transcription of cell– increasing production of ENaCs and Na+/ K+-ATPase pump
spirinalactone
competitive antagonist of mineralocorticoid receptor
epithelial soidium channels )ENaCs
widely expressed esp in kidney tubules (late DCT and CD) , lung and resp tract
increased ENaC expression on apical membrane due to activation of mineralocorticoid receptor increases Na+ permeability and Na+ reabsorption from tubule lumen into the cell
rate limiting step in salt reabsorption in this part of the nephron
these are NOT voltage gated
amiloride is a what
ENaC blocker potassium sparing
Na+Cl- ATPase (Na+ pump)
tansmembrane ATP-dependant active transporter
ubiquitously expressed
for each ATP, 3 Na+ out and 2k+ in
pumps Na+ out of cell into interstitium, keeping intracellular conc low so the NaKATPase pump can keep working
what drugs inhibit Na+Cl-ATPase pumps
cardiac glycosides e.g., digoxin
Liddle syndrome
rare genetic (autosomal dominant) disorder
causes severe hypertension from a young age
mutations prevent channel internalization and degradation
overexpression of ENaCs causes excess Na+ reabsorption
treat with ENaC blockers e.g., amiloride
Master slide
antihypertensive drugs
diURETICS (thiazides, loops, K sparing)
renin inhibitor
ACE inhibitos -pril
Angiotensin recptor blocker -sartan
B blockers -lol
calcium channel blockers -dipine
centrally acting a2 agonists e.g., clonidine
vasodilators
aliskiren
renin inhibitor
essential hypertension
target= renin action= competitive inhibitor
physiology: decrease production of AngI
enalapril
ACE inhibitor (most ACE inhibitors are pro drugs)
Prodrug
essential hypertension and heart failure
target: ACE Activity: competitive inhibitor
Physiology: decrease prod of AT-II and decrease breakdown of the vasodilator bradykinin
valsartan
angiotensin receptor blocker
essential hypertension + heart failure
target: AT1. activity: competitive antagonist
Physiology: decreases effects of AT-II…… no effect on bradykinin so no cough
atenolol
selective B1 blocker
essential hypertension - angina -arrthmias
target: B1 receptor as higher affinity than B2. activity: competitive antagonist
Gs coupled therefore antagonism of their activation reduces activity of adenylyl cyclase and its downstream signalling via cyclic adenosime monophosphate and protein kinase A (PKA)
not understood but decreases CO, alters baroreceptor reflexes and decreases renin secretion
amlodipine
calcium channel blocker
essential hypertension angina
target= L-type voltage gated calcium channel activity- gating inhibitor
greater specificity fpr sm over cardiac msucle
decreased calcium mobilisation in smooth muscle means vasodilation
voltage gated calcium channels
all open in response to depolarisation
L-type: once open stay open for a Long time, inactivate slowly
phosphorylated by action of adrenaline/ NA
amlodipine does not block but stabillises it in either
1) an unresponsive state
2) a hyper-responsive state
