(pharm) pharmacology of hypertension Flashcards
what are four classes of drugs that are commonly prescribed for hypertension?
angiotensin converting enzyme inhibitors (ACE inhibitors)
calcium channel blockers
thiazide/thiazide-like diuretics
angiotensin receptor blockers (ARBs)
give examples of ACE inhibitors
ramipril
lisinopril
perindopril
explain the primary mechanism of action of ACE inhibitors
inhibit angiotensin-converting enzyme
= prevent the conversion of angiotensin I to angiotensin II by ACE
what is the drug target for ACE inhibitors?
angiotensin-converting enzyme
what are the main side effects of ACE inhibitors?
cough
hypotension
hyperkalaemia
foetal injury (AVOID IN PREGNANT WOMEN)
renal failure (in patients w renal artery stenosis)
urticaria/angioedema
how do ACE inhibitors affect serum potassium levels and why is this important?
can cause hyperkalaemia as a side effect so care must be take with K+ supplements or K+ sparing diuretics
how do ACE inhibitors affect foetuses?
can cause foetal injury as a side effect and so pregnant women cannot take them
what must occur for most ACE inhibitors to have their therapeutic effect?
require hepatic activation (as they are pro-drugs) to generate the active metabolites required for therapeutic effects
ACE inhibitors are pro-drugs - what does this mean?
require hepatic activation to generate the active metabolites required for therapeutic effects
how do ACE inhibitors affect the kidneys?
can cause renal failure in patients with renal artery stenosis
what must be regularly monitored if ACE inhibitors are prescribed?
serum potassium levels and eGFR
what are the more anti-hypertensive agents: ARBs or ACE inhibitors?
according to most trials, ACE inhibitors > ARBs
give examples of calcium channel blockers
amlodipine
felodipine
explain the primary mechanism of action of calcium channel blockers
binds to and blocks L-type calcium channels (found predominantly on vascular smooth muscle)
= decrease in calcium influx
= increases downstream inhibition of myosin light chain kinase + prevention of cross-bridge formation
= resultant vasodilation reduces peripheral resistance
what is the drug target for calcium channel blockers?
L-type calcium channels (found predominantly on vascular smooth muscle)
what are the main side effects of calcium channel blockers?
ankle oedema
constipation
palpitations
flushing
headaches
what are the two types of calcium channel blockers?
dihydropyridine CCBs and non-dihydropyridine CCBs
differentiate between the two types of calcium channel blockers
dihydropyridine (DHP) CCBs tend to be more potent vasodilators than non-dihydropyridine (non-DHP) CCBs
(the latter have greater depressive effects on cardiac conduction and contractility and are less potent vasodilators)
why are dihydropyridine calcium channel blockers more potent vasodilators?
they have a higher degree of vascular selectivity
give examples of thiazide/thiazide-like diuretics
bendro-flu-methiazide (thiazide)
indapamide (thiazide-like)
explain the primary mechanism of action of thiazide/thiazide-like diuretics
bind to and block the Na+, Cl- co-transporter in the early DCT so Na+ and Cl- reabsorption into the blood is inhibited
= the osmolarity of the tubular fluid increases, steepening the osmotic gradient for water reabsorption in the collecting duct
= greater water reabsorption in the collecting duct reduces arterial pressure and therefore peripheral vascular resistance in the surrounding blood vessels
what is the drug target for thiazide/thiazide-like diuretics?
sodium-chloride co-transporter in the distal convoluted tubule
what are the main side effects of thiazide/thiazide-like diuretics?
hypokalaemia
hyponatraemia
metabolic alkalosis (increased H+ ion excretion)
hypercalcaemia
hyperglycaemia (hyperpolarised pancreatic beta cells)
hyperuricemia
how long do the effects of thiazide/thiazide-diuretics last?
both lose their diuretic effects within 1-2 weeks of treatment and remaining anti-hypertensive effects are due to vasodilating properties
give examples of angiotensin receptor blockers
losartan
irbesartan
candesartan
explain the primary mechanism of action of angiotensin receptor blockers (ARBs)
non-competitive antagonists at AT1 receptor (found on the kidneys and on the vasculature)
which region of the body do angiotensin receptor blockers act on?
on the AT1 receptors found on the kidneys and vasculature
what are the main side effects of angiotensin receptor blockers?
hypotension
hyperkalaemia (care w K+ supplements and K+ sparing diuretics)
foetal injury (avoid in pregnant women)
renal failure (in patients w renal artery stenosis)
losartan and candesartan are pro-drugs - what does this mean?
require hepatic activation to generate the active metabolites required for therapeutic effects
what are the classifications of hypertension?
stage 1 hypertension (140/90 to 160/100)
stage 2 hypertension (160/100 to 180/120)
severe hypertension (higher than 180/120)
what is stage 1 hypertension?
between 140/90 to 160/100
what is stage 2 hypertension?
between 160/100 to 180/120
what is severe hypertension?
higher than 180/120
what is Q risk?
an algorithm for predicting cardiovascular risk
what does Q risk estimate?
estimated the risk of an individual developing cardiovascular diseases over the 10 years
what is a concerning Q risk score?
an individual scoring above 10% is considered to be at high risk of cardiovascular disease
what is used to predict an individual’s cardiovascular risk?
a Q risk score
how would you manage a patient with a Q risk score of greater than 10%?
lifestyle modifications (more exercise, lose weight, improve diet, stop smoking, reduce alcohol intake)
drug treatment (maybe statin/other drugs depending on conditions)
what are the therapeutic objectives for a patient with stage 1 hypertension?
reduce blood pressure levels to below 140/90 ideally
modify lifestyle factors that are associated with an increased morbidity and mortality (i.e. smoking, weight, alcohol intake)
ensure no contraindications to medication prescribed (interference w surgery?)
why do calcium channel blockers have the greater effect on smooth muscle and cardiac muscle as opposed to skeletal muscle?
both smooth muscle and cardiac muscle rely on extracellular calcium (as well as intracellular calcium) for muscle contraction however skeletal muscle relies only on intracellular calcium stores
= so prevention of extracellular calcium influx will more significantly impair smooth + cardiac muscle contraction
(skeletal muscle may also have different types of calcium channels which CCBs cannot act on)
what is the mechanism of action of calcium channel blockers?
bind to and block L-type calcium channels, preventing an influx of extracellular calcium into the vascular smooth muscle cells
prevent the formation of of actin-myosin cross-bridges, reducing frequency and force of muscle contraction
= subsequently less vasoconstriction reduces peripheral vascular resistance
why is vasodilation important to tackle hypertension?
vasodilation will reduce the systemic vascular resistance by allowing for a increased in blood flow and therefore reduced blood pressure
what is plasma clearance in terms of pharmacology?
the measure of the ability of the body to eliminate a drug
what is elimination half-life in terms of pharmacology?
the length of time required for the concentration of a particular drug to decrease to half of its starting dose in the body
what is time to peak plasma levels in terms of pharmacology?
the time required for a drug to reach peak concentration in plasma
(i.e. faster absorption rate, less time to peak plasma concentration)
what is the relationship between absorption rate and time to peak plasma concentration?
faster absorption rate, less time to peak plasma concentration
what is the measure of plasma clearance?
ml/min/kg
what is the mechanism of action of ACE inhibitors in the treatment of hypertension?
bind to and inhibit angiotensin converting enzyme that prevents the conversion of angiotensin I to angiotensin II
with less angiotensin II, less aldosterone synthesis is stimulated = reduced vasoconstriction + reduced Na+ retention in the kidneys
why do calcium channel blockers cause oedema?
increased vasodilation = increased Starling forces within the bloodstream = increased capillary hydrostatic pressure resulting in oedema
why are angiotensin receptor blockers preferentially used over ACE inhibitors?
as ARBs will not simultaneously also reduced the conversion of bradykinin to inactive metabolites
what two factors have to be monitored in patients on ACE inhibitors?
serum potassium and eGFR
explain why eGFR has to be monitored in patients on ACE inhibitors
less angiotensin II = less constriction of the efferent arteriole so blood does not build up in glomerulus SO glomerular pressure cannot increase
= impaired/reduced glomerular filtration
explain why serum potassium has to be monitored in patients on ACE inhibitors
increased ACE inhibitors = less aldosterone synthesis
aldosterone stimulates Na+ reabsorption and K+ excretion in the renal collecting duct
so with less aldosterone, less Na+ reabsorption and LESS K+ excretion
= increased K+ retention risks hyperkalaemia
what effect does angiotensin II have on the glomerular arterioles?
angiotensin II will constrict the glomerular arterioles
will constrict the efferent arteriole MORE SIGNIFICANTLY than the afferent
= forces blood to build up in the glomerulus, increasing glomerular pressure
= required for glomerular filtration
which glomerular arteriole does angiotensin II more significantly affect?
efferent arteriole
explain what happens if an ACE inhibitor is given to a patient with renal artery stenosis
afferent arteriole already stenosed (i.e. already less blood is entering the glomerulus)
+ combined with reduced tone of efferent arteriole (due to ACEi)
= glomerular pressure cannot increase to sufficient levels to allow glomerular filtration to efficiently occur
(GFR collapses)
what is the mechanism of action of indapamide (thiazide-like diuretic)?
block the Na+, Cl- co-transporter in the early DCT
= Na+ and Cl- reabsorption is inhibited
so osmolarity of the tubular fluid increases, so steeper water potential gradient
= reduced water reabsorption in the collecting duct
= reduced arterial pressure
= reduced peripheral vascular resistance
what effect do thiazide-like diuretic have on serum potassium?
reduce serum potassium levels
what drug type is given to type II diabetes patients with hypertension and why?
respond better to ACEi than CCB as ACEi tend to be better for renal function which can be impaired in T2DM patients
what dietary modifications can patients with hypertension be encouraged to make?
follow DASH (dietary approaches to stop hypertension)
daily sodium < 1.5 grams
two of the most commonly prescribed ACE inhibitors are ramipril and lisinopril
ramipril (like most ACE inhibitors) is a pro-drug whereas lisinopril is not
what does this mean?
pro-drugs = drug is inactive until it is metabolised in the body (most commonly in the liver)
what is the opposite of a pro-drug?
explain how
pro-drug = drug is inactive until it is metabolised by the liver
active drug = drug is active and it takes effect directly
what are the three main impacts of thiazide-like diuretics?
as a result of the inhibition of the apical Na+/Cl- symporters, and the subsequent urinary Na+ and water loss,
1) decreased blood volume
2) decreased venous return
3) decreased cardiac output
indapamide (and other thiazide-like diuretics) are excreted unchanged in the urine
why is this a vital part of the therapeutic action of thiazide-like diuretics?
the target site of action for thiazide-like diuretics is apical transporters in the kidney
the only way to get to this site of action is via glomerular filtration into the Bowman’s capsule and beyond
= if they are excreted unchanged, they will be able to have the desired effect at the desired site of action
why do thiazide-like diuretics increase potassium excretion?
thiazide-like diuretics act on the early DCT apical Na+/Cl- symporters to increase urinary sodium loss
= increased Na+ delivery from the early DCT to the distal DCT
= subsequent increased tubular Na+ concentration activates aldosterone-sensitive sodium pump to increase sodium reabsorption in exchange for potassium + hydrogen excretion
= increased potassium excretion
(!! increased hydrogen ion loss causes metabolic alkalosis !!)
how long does the effect of thiazide diuretics last and why?
the diuretic effect lasts around 1-2 weeks
= as eventually the kidney becomes tolerant to the diuretic effect and there is subsequent rebound activation of the renin-angiotensin system which increases sodium reabsorption, counteracting the diuretic effect
despite the diuretic effect of thiazide-like diuretics lasting only 1-2 weeks, what can the continued (after 2 weeks) antihypertensive effect be attributed to?
(less well understood) vasodilating effects
