Pharmacology Use of Beta-blockers & ARBs in cardiovascular disease

Treating Hypertension

Leading causes of death: Heart disease > Cancer > Respiratory disorders

Autonomic & hormonal control of cardiovascular function

2 feedback loops that compensate for changes in arterial BP.
When BP is decreased:
o Increased sympathetic outflow
o Renin release
When BP is elevated:
o Reduced sympathetic outflow
o Reduced renin release
o Increased parasympathetic (vagal) outflow.

Angiotensin II
Increases peripheral vascular resistance TPR
Facilitates sympathetic effects (not shown)

HYPERTENSION
Initiated & sustained (at least in part) by sympathetic
neural activation
In moderate to severe HPT, most effective drugs (see
image 2^) = agents inhibiting function of sympathetic NS
o Clonidine can affect the sympathetic NS
centrally, non-specifically, with side effects
o Affecting production of angiotensin II or blocking
receptors directly

Renin-Angiotensin System
Balanced vasodilators
o Vasodilation of both venous & arterial circuits
TPR BP
o Inhibitors of the renin-angiotensin-aldosterone
system:
1. Angiotensin Converting Enzyme (ACE) inhibitors
2. Angiotensin 2 (Type 1) Receptor Blockers (ARB)

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Hypertension Medications
A Alpha agonists, Alpha antagonists/blockers, ACE inhibitors, Angiotensin 2 (Type 1) Receptor Blockers (ARB)
B Beta (adrenergic receptor) antagonists/blockers
C Calcium channel blockers
D Diuretics (e.g. thiazide-type)
E Endothelin antagonists

A Alpha agonists: Centrally Acting Sympathoplegic Drugs

Rarely used nowadays, except for clonidine
Clonidine functions in the CNS at the vasomotor center & reduces sympathetic outflow to periphery.
Acts at alpha 2 receptors. Functionally, like having an alpha antagonist.
o This is because alpha 2 receptors are often inhibitory autoreceptors.
The released neurotransmitters act on the autoreceptor and inhibit further release of NE.
Antihypertensive agent despite its local vasoconstrictive action at alpha 2 receptors:
o At normal doses, clonidine lowers BP:
Decreased HR, relaxation of capacitance vessels & reduction in TPR => reduced CO => reduced
discharge of sympathetic system.
o At higher doses (usually not seen at therapeutic doses, but in massive overdose), clonidine increases BP:
Via local vasoconstriction effect on blood vessels at the alpha 2 receptors.
Impact on RAA system:
o Reduction in BP accompanied by renal vascular resistance & maintenance of renal blood flow.
(+) Advantage:
o BP reduced in the supine position. Rarely causes postural hypotension.
(-) Side-effects:
o Dry mouth & sedation (b/c both effects are centrally mediated & dose-dependent, coinciding
temporally with the antihypertensive effect)
Counter-indications:
o Should not be given to patients at risk for (or with) mental depression
Concomitant treatment with tricyclic antidepressants may block the antihypertensive effect,
because of the alpha-adrenoreceptor-blocking actions of the tricyclics.
Withdrawal syndrome: life-threatening hypertensive crisis (due to rebound sympathetic nervous activity)
o Nervousness, tachycardia, headache & sweating after omitting 1-2 doses of drug
o Important to stop the drug gradually.
o Treat hypertensive crisis w/ reinstitution of clonidine therapy or - & -adrenoreceptor-blocking agents

A - Alpha antagonists/blockers
Prazosin, terazosin & doxazosin
Reduce BP by selectively blocking 1 receptors in arterioles & venules, thus DILATING both resistance &
capacitance vessels.
Impact on RAA system:
o Retention of salt & water when blockers administered without a diuretic
Thus, blockers are more effective when combined with other agents ( blockers or diuretic).
(+) Advantage:
o Produce less reflex tachycardia when lowering BP than do nonselective antagonists, like
phentolamine (blocking 1 & 2, not used anymore)
o Nonselective agents, e.g. phentomaline, treat pheochromocytoma exaggerated catecholamine release
o Phentolamine blocker may be combined with propranolol blocker to treat clonidine withdrawal.
o As expected, BP is reduced more in the upright than in the supine position.
(-) Side-effects:
o First-dose phenomenon (unclear mechanism):
Precipitous drop in standing BP shortly after the 1st dose is absorbed.
Occurs more commonly in patients who are salt- and volume-depleted.
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 Thus, the 1st dose should be small & administered at bedtime.
o Mild & infrequent toxicities of 1 blockers
Dizziness, palpitations, headache, lassitude
Pro-indications:
o Use primarily in men with concurrent hypertension & benign prostatic hyperplasia
o Also helps men with their bladder obstruction symptoms

A - ACE inhibitors
Decrease BP by TPR (CO & HR not changed significantly)
Impact on RAA system:
o Most effective in patients w/ plasma renin activity, but correlation is week. Renin profiling unnecessary.
(+) Advantage:
o Unlike direct vasodilators, these agents do not cause reflex sympathetic activation.
Can be used safely in people with ischemic heart disease.
Absence of reflex tachycardia may be due to downward resetting of the baroreceptors or
enhanced parasympathetic activity.
(-) Side-effects:
o **Hypotension in patients with hypovolemia (as a result of diuretics, salt restriction, or GI fluid loss)
o Dry cough (with wheezing sometimes) & angioedema
Due to bradykinin & substance P seen with ACE inhibition
o Acute renal failure
o Hyperkalemia (more likely to occur in patients who already have renal insufficiency or diabetes)
o Minor toxic effects:
Altered sense of taste, allergic skin rashes, drug fever (in up to 10% of patients)
Pro-indications:
o Used in patients with chronic kidney disease: ACE inhibitors diminish proteinuria & stabilize renal
function (even in the absence of BP lowering)
o Used in diabetes (even in the absence of hypertension, only as a prophylaxis)
Counter-indications:
o ACE inhibitors shouldnt be administered in the 2nd & 3rd trimesters of pregnancy
Risk of fetal hypotension, anuria, renal failure, and occasionally fetal malformations or death.
o Drug interactions with K+ supplements or K-sparing diuretics, which can result in hyperkalemia.
o Nonsteroidal anti-inflammatory drugs may impair the hypotensive effects of ACE inhibitors by blocking
bradykin-mediated vasodilation, which may be prostaglandin-mediated.

A - Angiotensin II Receptor Blockers (ARBs)

More selective blockers of angiotensin effects than ACE inhibitors -> no effect on bradykinin metabolism
(+) Advantages:
o Similar benefits those of ACE inhibitors in patients with heart failure & chronic kidney disease.
o More complete inhibition of angiotensin action compared to ACE inhibitors, because other enzymes are
capable of generate angiotensin II.
(-) Side-effects:
o Similar to those described in ACE inhibitors
o Cough & angioedema are less common
Counter-indications:
o Hazard of use during pregnancy

B Beta (adrenergic receptor) antagonists/blockers

All -adrenoreceptor-blocking agents lower BP in mild to moderate hypertension.
Only some blockers work in heart failure.

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Propranolol - first blocker shown to be effective in hypertension & ischemic heart disease.
Propranolol decreases BP primarily by CO. Other blockers either CO or TRP.
blockers may also reduce sympathetic peripheral vasoconstriction (to skin or viscera) by acting on peripheral
presynaptic adrenoreceptors.
Impact on RAA system:
o Propanolol inhibits renin production by catecholamines (mediated by 1 receptors)
This results in depression of the renin-angiotensin-aldosterone (RAA) system.
This is why propranolol is MOST effective in patients with high plasma renin activity.
Although it still works in hypertensive patients with normal or low renin activity.
(+) Advantage:
o In mild to moderate hypertension, significant reduction in BP without postural hypotension.
o In severe hypertension, blockers prevent the reflex tachycardia that would occur with direct
vasodilators. Thus, no pounding heart!
(-) Side-effects:
o Resting bradycardia & HR during exercise
Due to blockage of cardiac, vascular or bronchial receptors.
Note: normally sympathetic drive increases HR, relaxes skeletal muscle vessels, and relaxes
bronchiolar smooth muscle at the B2 receptor.
o Myocardial infarction reported in a few patients.
o blocking action occurs in patients with bradycardia, or cardiac conduction disease, asthma, peripheral
vascular insufficiency, and diabetes.
Withdrawal syndrome: up-regulation or supersensitivity of adrenoreceptors due to removal of inhibition
o Nervousness, tachycardia, intensity of angina, BP.

Metoprolol & atenolol: cardioselective blockers (most widely used blockers in HPT, have replaced propanolol)
Although cardioselectivity is not complete, metoprolol causes less bronchial constriction that propranolol.
o Metoprolol is a 1 selective blocker, while bronchial constriction is enhanced by 2 antagonism.
Atenolol is less effective than metoprolol in preventing complications of hypertension.

SUMMARY:
Initial therapy (3 options):
o D - Thiazide-type diuretic
o C Calcium channel blocker
o A ACE inhibitor or ARB (favoured over other drug classes in patients with HPT + diabetes)
blockers no longer recommended as initial therapy, except in patients with another indication, e.g. coronary
heart disease or left ventricular dysfunction.
More than 1 drug may be needed to control BP in hypertensive patients.
o Generally, if the 1st drug doesnt achieve BP goads, adding a 2nd drug with a diff. mechanism of action is
more effective in BP (than increasing the dose of 1st drug).
Dont use 2 renin-angiotensin system inhibitors together (e.g. ACE inhibitor + ARB). When 1 such drug was
used, when adding a 2nd drug, chose a diuretic or calcium channel blocker.
When baseline BP > 20/10 mmHg above goal, begin therapy with 2 drugs.

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 HEART FAILURE & THERAPY
Proportion of patients with diastolic failure increases with age. Heart failure is increasing in prevalence!
o Thanks to better treatment of other cardiovascular conditions like MIs, patients survive long enough for
heart failure to develop.
While we can treat hypertension, we still dont have the perfect treatment for chronic heart failure.

ACE inhibitors along with diuretics => first-line therapy for chronic HF.
By reducing preload & afterload in asymptomatic patients, ACE inhibitors slow the progress of ventricular dilation and
thus slow the downward spiral of heart failure.
ACE inhibitors benefits in all subsets of patients from asymptomatic to severe chronic failure.

Biased ligands
Consult notes

* Note: Were still mostly treating symptoms in hypertension & heart failure.

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