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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g.  Occurs more commonly in patients who are salt.Hypertension Medications A – Alpha agonists. Angiotensin 2 (Type 1) Receptor Blockers (ARB) B – Beta (adrenergic receptor) antagonists/blockers C – Calcium channel blockers D – Diuretics (e. thus DILATING both resistance & capacitance vessels. phentomaline. thiazide-type) E – Endothelin antagonists A – Alpha agonists: Centrally Acting Sympathoplegic Drugs  Rarely used nowadays. treat pheochromocytoma – exaggerated catecholamine release o Phentolamine α blocker may be combined with propranolol β blocker to treat clonidine withdrawal. clonidine increases BP:  Via local vasoconstriction effect on blood vessels at the alpha 2 receptors. o Treat hypertensive crisis w/ reinstitution of clonidine therapy or α. o At higher doses (usually not seen at therapeutic doses.  (-) Side-effects: o First-dose phenomenon (unclear mechanism):  Precipitous drop in standing BP shortly after the 1st dose is absorbed. relaxation of capacitance vessels & reduction in TPR => reduced CO => reduced discharge of sympathetic system. like having an alpha antagonist.& β-adrenoreceptor-blocking agents A .  Impact on RAA system: o Retention of salt & water when α blockers administered without a diuretic  Thus. because of the alpha-adrenoreceptor-blocking actions of the tricyclics.  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.g. BP is reduced more in the upright than in the supine position.  Acts at alpha 2 receptors. 2 of 5 .  (+) Advantage: o BP reduced in the supine position. o This is because alpha 2 receptors are often inhibitory autoreceptors. Functionally. headache & sweating after omitting 1-2 doses of drug o Important to stop the drug gradually. terazosin & doxazosin  Reduce BP by selectively blocking α1 receptors in arterioles & venules. e. except for clonidine  Clonidine functions in the CNS at the vasomotor center & reduces sympathetic outflow to periphery. α blockers are more effective when combined with other agents (β blockers or diuretic).and volume-depleted. but in massive overdose).  Impact on RAA system: o Reduction in BP accompanied by ↓ renal vascular resistance & maintenance of renal blood flow. like phentolamine (blocking α1 & 2. ACE inhibitors. o As expected.Alpha antagonists/blockers  Prazosin. 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. clonidine lowers BP:  Decreased HR.  (+) Advantage: o Produce less reflex tachycardia when lowering BP than do nonselective α antagonists. not used anymore) o Nonselective agents.  Withdrawal syndrome: life-threatening hypertensive crisis (due to rebound sympathetic nervous activity) o Nervousness.  (-) Side-effects: o Dry mouth & sedation (b/c both effects are centrally mediated & dose-dependent. tachycardia. Alpha antagonists/blockers. Rarely causes postural hypotension.

allergic skin rashes.  (+) Advantage: o Unlike direct vasodilators. anuria. 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. o More complete inhibition of angiotensin action compared to ACE inhibitors. renal failure. these agents do not cause reflex sympathetic activation. palpitations. headache. o Mild & infrequent toxicities of α1 blockers  Dizziness. which can result in hyperkalemia. but correlation is week.  Only some β blockers work in heart failure.ACE inhibitors  Decrease BP by ↓TPR (CO & HR not changed significantly)  Impact on RAA system: o Most effective in patients w/ plasma renin activity. because other enzymes are capable of generate angiotensin II. 3 of 5 .  Can be used safely in people with ischemic heart disease. o Nonsteroidal anti-inflammatory drugs may impair the hypotensive effects of ACE inhibitors by blocking bradykin-mediated vasodilation.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.  Absence of reflex tachycardia may be due to downward resetting of the baroreceptors or enhanced parasympathetic activity. Renin profiling unnecessary. 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. and occasionally fetal malformations or death. which may be prostaglandin-mediated.  (-) Side-effects: o **Hypotension in patients with hypovolemia (as a result of diuretics. salt restriction.  (-) 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 β-adrenoreceptor-blocking agents lower BP in mild to moderate hypertension. the 1st dose should be small & administered at bedtime. o Drug interactions with K+ supplements or K-sparing diuretics. only as a prophylaxis)  Counter-indications: o ACE inhibitors shouldn’t be administered in the 2nd & 3rd trimesters of pregnancy  Risk of fetal hypotension.  Thus. A . lassitude  Pro-indications: o Use primarily in men with concurrent hypertension & benign prostatic hyperplasia o Also helps men with their bladder obstruction symptoms A .

vascular or bronchial β receptors.  Impact on RAA system: o Propanolol inhibits renin production by catecholamines (mediated by β1 receptors)  This results in depression of the renin-angiotensin-aldosterone (RAA) system. o Myocardial infarction reported in a few patients. begin therapy with 2 drugs. when adding a 2nd drug. relaxes skeletal muscle vessels. while bronchial constriction is enhanced by β2 antagonism. coronary heart disease or left ventricular dysfunction. SUMMARY:  Initial therapy (3 options): o D .  Withdrawal syndrome: up-regulation or supersensitivity of adrenoreceptors due to removal of inhibition o Nervousness.  Note: normally sympathetic drive increases HR. and relaxes bronchiolar smooth muscle at the B2 receptor.  When baseline BP > 20/10 mmHg above goal.g. e.first β blocker shown to be effective in hypertension & ischemic heart disease. o In severe hypertension. Metoprolol & atenolol: cardioselective β blockers (most widely used β blockers in HPT. have replaced propanolol)  Although cardioselectivity is not complete.  More than 1 drug may be needed to control BP in hypertensive patients.Thiazide-type diuretic o C – Calcium channel blocker o A – ACE inhibitor or ARB (favoured over other drug classes in patients with HPT + diabetes)  β blockers no longer recommended as initial therapy.  Atenolol is less effective than metoprolol in preventing complications of hypertension. Other β blockers either ↓CO or ↓TRP.  (+) Advantage: o In mild to moderate hypertension. or cardiac conduction disease. significant reduction in BP without postural hypotension. ↑ intensity of angina.  This is why propranolol is MOST effective in patients with high plasma renin activity. Thus. except in patients with another indication. peripheral vascular insufficiency.g. o Generally.  Propranolol decreases BP primarily by ↓CO. β blockers prevent the reflex tachycardia that would occur with direct vasodilators. tachycardia. ↑BP. chose a diuretic or calcium channel blocker.  Don’t use 2 renin-angiotensin system inhibitors together (e. if the 1st drug doesn’t achieve BP goads.  Although it still works in hypertensive patients with normal or low renin activity. ACE inhibitor + ARB). mechanism of action is more effective in ↓BP (than increasing the dose of 1st drug). metoprolol causes less bronchial constriction that propranolol. 4 of 5 . and diabetes. o β blocking action occurs in patients with bradycardia. no pounding heart!  (-) Side-effects: o Resting bradycardia & ↓HR during exercise  Due to blockage of cardiac.Propranolol . adding a 2nd drug with a diff. asthma.  β blockers may also reduce sympathetic peripheral vasoconstriction (to skin or viscera) by acting on peripheral presynaptic β adrenoreceptors. When 1 such drug was used. o Metoprolol is a β1 selective blocker.

we still don’t have the perfect treatment for chronic heart failure.  While we can treat hypertension. 5 of 5 . Heart failure is increasing in prevalence! o Thanks to better treatment of other cardiovascular conditions like MIs. Biased ligands  Consult notes * Note: We’re still mostly treating symptoms in hypertension & heart failure. By reducing preload & afterload in asymptomatic patients. ACE inhibitors along with diuretics => first-line therapy for chronic HF. ACE inhibitors benefits in all subsets of patients – from asymptomatic to severe chronic failure. HEART FAILURE & THERAPY  Proportion of patients with diastolic failure increases with age. patients survive long enough for heart failure to develop. ACE inhibitors slow the progress of ventricular dilation and thus slow the downward spiral of heart failure.