Pharmacology – HYPERTENSION & ANTIHYPERTENSIVES (MADE EASY)

Pharmacology – HYPERTENSION & ANTIHYPERTENSIVES (MADE EASY)


in this lecture I’m going to talk about
pharmacology of antihypertensive drugs so let’s get right into it
hypertension or high blood pressure is a quite common disorder affecting many
people who typically don’t even notice any symptoms now in order to gain a
better understanding of pharmacology of antihypertensive agents first we need to
review a basic physiology of blood pressure regulation so when we talk
about blood pressure we are generally referring to the force or tension of
blood pressing against the artery walls now this pressure in the arteries is
maintained by among other things contraction of the left ventricle
systemic vascular resistance elasticity of the arterial walls as well blood
volume in other words blood pressure is simply a product of cardiac output and
systemic vascular resistance there are a couple of major systems involved in
blood pressure regulation first arterial blood pressure is regulated by pressure
sensitive neurons called baroreceptors located in the aortic arch and carotid sinuses so for example if blood pressure falls too low those baroreceptors can
send signals to the adrenal medulla causing release of catecholamines and
thus increase in sympathetic activity through activation of alpha and beta receptors
so activation of beta-1 receptors causes increase in heart rate and stroke volume
and thus increased cardiac output which leads to increase in blood pressure on
the other hand activation of alpha-1 receptors on smooth muscle causes
vasoconstriction and thus increase in vascular resistance which again leads to
increase in blood pressure now another major system involved in blood pressure
regulation is the renin-angiotensin-aldosterone system so
we also have baroreceptors in the kidneys that respond to fall in blood
pressure or reduction of blood flow by releasing enzyme called renin
additionally renin secretion is also stimulated by sympathetic activation of
beta-1 receptors in the kidneys now renin is necessary
for the production of angiotensin II angiotensin II is a very potent vasoconstrictor which constricts systemic blood vessels thus increasing peripheral
resistance angiotensin II also constricts renal blood vessels and
stimulates aldosterone secretion which leads to sodium and water retention
thereby increased blood volume cardiac output and ultimately increased blood
pressure now let’s switch gears and let’s talk about antihypertensive
agents so there are several major classes of antihypertensive drugs which
work by interrupting different parts of this blood pressure regulating system
first we have alpha-1 blockers such as Doxazosin and Prazosin which block
alpha-1 receptors on the smooth muscle thus causing decrease in systemic
vascular resistance and ultimately decrease in blood pressure next we have
selective beta blockers such as Atenolol and Metoprolol which selectively block
beta-1 receptors on the heart thus causing decrease in cardiac output and
thereby decrease in blood pressure as you may remember we also have
non-selective beta blockers such as Labetalol and Carvedilol that can
additionally block alpha-1 receptors and thus simultaneously decrease vascular
resistance furthermore beta blockers can inhibit beta-1 receptors present on the
kidneys and thus suppress release of renin formation of angiotensin II and
secretion of aldosterone so these effects result in decrease in systemic
vascular resistance and again fall in blood pressure to learn more about alpha
and beta blockers make sure you check out my video about adrenergic
antagonists now the next major class of antihypertensive agents are centrally
acting adrenergic drugs which work by blocking sympathetic activity within the
brain example of drugs that belong to this class are Clonidine and Methyldopa
now Clonidine selectively stimulates presynaptic alpha-2 receptors thus
providing negative feedback to reduce catecholamine production and release
this leads to decrease in systemic vascular resistance and
cardiac output and ultimately decreased blood pressure Methyldopa on the other hand also lowers blood pressure through the same mechanism
however unlike Clonidine it is not an agonist itself so first it must be
converted to its active metabolite called methylnorepinephrine now let’s
move on to another major class of antihypertensive agents that is calcium
channel blockers so calcium channel blockers are divided into two main
subclasses dihydropyridines and nondihydropyridines now dihydropyridines
selectively inhibit L-type calcium channels in the vascular smooth muscle
under normal conditions when calcium enters the smooth muscle cell it causes
it to contract which leads to increased vascular resistance and thus increase in
blood pressure so when dihydropyridine drug blocks the entry of calcium into the
vascular smooth muscle cell the contraction is inhibited which leads to
decreased resistance to blood flow and thus lowering of blood pressure example
of drugs that belong to this group are Amlodipine Felodipine Nicardipine
and Nifedipine when it comes to side effects of dihydropyridines they’re
related to systemic vasodilation so you can expect dizziness headache flushing
and peripheral edema another side effect that may occur with this class is
swelling of gums also known as gingival hyperplasia now let’s move on to nondihydropyridines which are non selective inhibitors of L-type calcium channels in
other words they are not only capable of blocking calcium channels on vascular
smooth muscle but also calcium channels on cardiac cells such as those of SA
node and AV node which leads to reduced myocardial contractility slower heart
rate and slower conduction that’s why these agents exhibit significant
antiarrhythmic properties for more details make sure you check out my video
about antiarrhythmic drugs now it’s important to remember that even
though decreased heart contractions typically result in decreased cardiac
output nondihydropyridines do not
significantly decrease cardiac output most likely because of the reflex
tachycardia that occurs as a result of vasodilation currently there are only
two drugs that belong to this group namely Diltiazem and Verapamil now when
it comes to side-effects nondihydropyridines can cause excessive bradycardia
and cardiac conduction abnormalities additionally Verapamil which happens to
be the least selective calcium channel blocker can exert significant inhibition
of calcium channels in the smooth muscle that lines the GI tract which can lead
to constipation now the next major class of antihypertensive agents are diuretics there are three major classes of diuretics
that are used in the treatment of hypertension first we have loop
diuretics such as Furosemide which work by reducing reabsorption of sodium
chloride in the kidneys leading to significant diuresis with less volume in
the vascular space less blood returns to the heart so cardiac output decreases
this in turn leads to decrease in blood pressure particularly in patients with
volume-based hypertension and chronic kidney disease secondly we have thiazide
diuretics such as Hydrochlorothiazide which also reduce reabsorption of sodium
chloride in the kidneys but to a much smaller degree than loop diuretics this
leads to initial decrease in intravascular volume decrease in cardiac
output and ultimately lower blood pressure however the long term effects
on blood volume are minimal and sustained antihypertensive effects are
thought to be produced by thiazide induced vasodilation lastly we have potassium-sparing diuretics such as Triamterene and Spironolactone which increase
diuresis by either interfering with the sodium potassium exchange in the kidneys
or by blocking the actions of aldosterone potassium-sparing diuretics are often used in combination with loop and thiazide diuretics to reduce
loss of potassium that can occur with the use of these drugs for more details
make sure you check out my video about
diuretics now let’s move on to another group of antihypertensive agents that
is agents that work on the renin-angiotensin-aldosterone system so
here we have three pharmacological targets that can be used to reduce the
activity of angiotensin II which is ultimately responsible for causing blood
pressure to increase first we have renin the enzyme responsible for conversion of
angiotensinogen to precursor of angiotensin II that is angiotensin I so
renin is the target of renin inhibitors which selectively inhibit this enzyme
thus decreasing production of angiotensin II the example of drug that
belongs to this class is Aliskiren secondly we have angiotensin-converting enzyme that is responsible for conversion of angiotensin I to
angiotensin II this enzyme is the target of ACE inhibitors so just like
inhibition of renin inhibition of angiotensin-converting enzyme also leads
to decreased production of angiotensin II however what makes ACE inhibitors
different is that in addition to lowering angiotensin II levels they
can also elevate bradykinin levels bradykinin is a peptide that causes
blood vessels to dilate by stimulating the release of nitric oxide and
prostacyclin however normally angiotensin-converting
enzyme inactives bradykinin so it’s inhibition leads to bradykinin induced
vasodilation the example of drugs that belong to this class are Benazepril Captopril Enalapril Lisinopril Quinapril and Ramipril
finally we have angiotensin II receptors type 1 or
AT1 receptors for short so binding of angiotensin II to these receptors is
actually responsible for most of the effects of angiotensin II including
vasoconstriction and stimulation of aldosterone release these receptors are
the target of angiotensin II receptor blockers or ARBs for short the example
of drugs that belong to this class are Candesartan
Irbesartan Losartan Olmesartan and Valsartan
so in summary the agents that work on this renin-angiotensin-aldosterone
system either block the production of angiotensin II or block its actions on
the AT1 receptors this in turn leads to decreased systemic vascular resistance
but without significant changes in cardiac output additionally these agents
reduce the effects of angiotensin II on renal hemodynamics specifically
angiotensin II constricts the efferent arteriole thereby generating back
pressure in the glomerulus which can lead to injury so by reducing activity
of angiotensin II these agents also improve renal blood flow and thereby
reduce the risk of renal injury now when it comes to side effects because these
agents suppress aldosterone release their use can contribute to
development of hyperkalemia furthermore ACE inhibitors in particular may cause
dry cough or in rare cases angioedema which can be life-threatening
this is thought to be due to increased levels of bradykinin and substance P now
before we end this lecture I wanted to briefly discuss few other antihypertensive agents that do not fall into any of the classes that we covered
thus far so first we have Bosentan which is a competitive antagonist of a
potent vasoconstrictor called endothelin-1 which acts on the endothelin-A and endothelin-B receptors located on pulmonary vascular cells by blocking
the action of endothelin-1 on these receptors Bosentan leads to
vasodilation which decreases pulmonary vascular resistance for that reason Bosentan is often a drug of choice for treatment of pulmonary hypertension next
we have Fenoldopam which is a selective dopamine-1 receptor agonist the
dopamine-1 receptors are located on the smooth muscle cells in the peripheral
vasculature as well as the renal coronary cerebral and
mesenteric arteries by stimulating dopamine-1 receptors Fenoldopam
produces generalized arterial vasodilation which leads to decreased peripheral
resistance and thus lower blood pressure additionally Fenoldopam inhibits
tubular sodium reabsorption which results in natriuresis and diuresis
due to its rapid onset of action and short duration of action
Fenoldopam is often used in the hospitals for short-term management of
severe hypertension another fast-acting agents that are also used for
hypertensive emergency are Sodium Nitroprusside and Nitroglycerin which simply serve as a source of nitric oxide a potent peripheral vasodilator lastly
we have direct acting smooth muscle relaxants namely Hydralazine with
mechanism of action that has not been entirely determined yet and Minoxidil
which works by stimulating opening of ATP-activated potassium channels in the
smooth muscle which leads to membrane stabilization making vasoconstriction
less likely while these agents significantly decrease peripheral
resistance they also produce significant compensatory reflex tachycardia and
renin release for that reason these drugs are typically administered in
combination with a diuretic and a beta blocker on the flip side topical
application of Minoxidil promotes hair growth which is why this drug is used
more often for treatment of baldness rather than hypertension and with that I
wanted to thank you for watching I hope you enjoyed this video and as always
stay tuned for more