Chapter 7

what are adrenergic antagonists?

• aka adrenergic blockers or sympatholytics

• bind to adrenoceptors but do not trigger the usual receptor-mediated intracellular effects

• act reversibly or irreversibly binding to adrenoceptors, preventing activation by endogenous or exogenous agonists

• classified according to their relative affinities for a or B receptors in SNS

general alpha blockers

• alfuzosin

• doxazosin

• phenoxybenzamine

• prazosin

• silodosin

• tamsulosin

• terazosin

general beta blockers

• acebutolol

• atenolol

• betaxolol

• bisoprolol

• cartelol

• carvedilol

• esmolol

• labetalol

• levobunolol

• metoprolol

• nadolol

• nebivolol

• pindolol

• propranolol

• timolol

effects of adrenergic antagonists

• pupils do no dilate

• increased GI secretions

• loss of bronchodilation

• decreased venous return related to vasodilation

• lowered BP

• increased GI activity

• decreased glucose regulation

• relaxed sphincters to increase GI excretions

• relaxed sphincters to increase urine flow

• decreased sexual response

alpha adrenergic blocking agents

• nonselective a-blockers decrease peripheral resistance and increase CO

  • goes on a₁ and a₂ receptors, epi cannot bind

• drugs that block a₁ adrenoceptors profoundly affect blood pressure

• selective a₂ adrenergic blockers have limited clinical utility

• phenoxybenzamine→ nonselective, noncompetitive blocker

• phentolamine→ nonselective, competitive blocker

• prazosin, terazosin, doxazosin→ selective competitive a₁ blocker

• yohimbine→ selective competitive a₂ blocker

phenoxybenzamine

• nonselective irreversible antagonist

  • binds irreversibly to receptor w/ covalent bond formation

• cardiovascular effects:

  • block of a₁ receptor, vasoconstriction of peripheral blood vessels caused by endogenous catecholamines→ decreased peripheral resistance→ reflex tachycardia

    • (the decreased peripheral resistance causes an imbalance in BP, body senses it falling and increases it)

  • block of presynaptic a₂ receptors on the sympathetic nerve terminals in the heart→ increased NE release

  • increased HR and CO (mediated by B₁ receptors)

  • cardiac arrhthymias and anginal pain (heart has more work/stress)

  • unsuccessful in maintaining lowered BP in HTN, no longer used for this purpose

• epinephrine reversal:

  • all a-adrenergic blockers reverse the a agonist actions of epi

  • vasoconstrictive action of epi is interrupted but vasodilation of other vascular beds (controlled by B receptors) is not blocked

• therapeutic uses:

  • tx of sweating and HTN associated w/ pheochromocytoma

• adverse effects:

  • postural hypotension

  • nasal stuffiness, nausea, vomitting

  • may inhibit ejaculation

  • reflex tachycardia

  • used w/ caution in pts w/ cerebrovascular or cardiovascular disease

pheochromocytoma

catecholamine-secreting tumor (cancer) of cells derived from adrenal medulla; increases release of adrenaline

phentolamine

• nonselective, competitive blocker of a₁ and a₂ receptors

  • binds to same spot as endogenous ligand

• cardiovascular actions:

  • similar to those of phenoxybenzamine

• therapeutic uses:

  • diagnosis and short term management of pheochromocytoma

  • locally to prevent dermal necrosis following extravasation of norepinephrine

    • counters NE (agonist) w/ antagonist and keeps the vein open

  • tx of hypertensive crisis due to abrupt withdrawal of clonidine or ingestion of tyramine-containing foods in patients taking monoamine oxidase inhibitors

    • leads to rebound HTN

hypertensive crisis

HTN caused by overstimulation of the SNS

extravasation of NE

occurs when NE is administered via IV infusion; NE leaks into subcutaneous tissue causing severe local vasoconstriction, tissue ischemia and necrosis

prazosin, terazosin, doxazosin

• selective competitive blockers of a₁ receptor

• metabolism leads to inactive products that are excreted in urine, except for those of doxazosin which appears in feces

• doxazosin is the longest-acting of the 3

• actions:

  • decrease of peripheral vascular resistance and lowering of BP→relaxation of both arterial and venous smooth muscle

  • minimal changes in CO, renal blood flow and glomerular filtration rate

• therapeutic uses:

  • tx of HTN

  • first dose of these drugs may produce exaggerated orthostatic hypotensive response resulting in syncope→ “first-dose” effect

    • solutions includes: lower doses, take before bed

  • a₁ antagonists are not used as monotherapy for tx of HTN

• adverse effects:

  • a₁ blockers may cause dizziness, fatigue, nasal congestion, headache, drowsiness, and orthostatic hypotension

  • additive antihypertensive effect occurs when a₁ antagonists are given w/ vasodilators such as nitrates or PDE-5 inhibitors (ex: sildenafil)

    • antihypertensive = drop in BP

    • nitrates are used as tx for cardiovascular disease

beta adrenergic blocker characteristics

• all the clinically available B-blockers are competitive antagonists

• nonselective B blockers act at both B₁ and B₂ receptors

• cardioselective B antagonists primarily block B₁ receptors

• there are no clinically useful B₂ antagonists

• all B blockers lower BP in hypertension, no postural hypotension because the a-adrenoceptors remain functional

• B blockers are also effective in tx angina, cardiac arrhythmias, myocardial infarction, congestive heart failure, hyperthyroidism, glaucoma, serve in the prophylaxis of migraine headaches

actions of B-blockers in the heart

• decreases HR

• decreases force of contraction

• decreases rate of AV conduction

negative iotrophic, chronotrophic, dronotrophic effects

side effects of B-blockers

• bradycardia

• lethargy

• GI disturbance

• low BP

• depression

nonselective beta blockers

• nadolol

• penbutolol

• pindolol

• propranolol

• timolol

• sotalol

• levobunolol

• metipranolol

propranolol

• actions:

  • cardiovascular (diminished CO)

  • initial reflex peripheral vasoconstriction

  • bronchoconstriction

  • decrease in glycogenolysis and glucagon secretion

• therapeutic uses:

  • HTN

  • angina → decreased O₂ requirement

  • myocardial infarction

  • migraine (prophylaxis, penetrates CNS)

  • hyperthyroidism

• adverse effects:

  • arrhythmias (due to abrupt interruption of therapy)→gradually reduce dosage over a period of a few weeks

  • bronchoconstriction (due to B₂ in lungs)→ contraindicated for COPD and asthma

  • metabolic disturbances→ hypoglycemia and increased low-density lipoproteins

  • CNS effects such as lethargy, depression

  • sexual impairment

angina

chest pain because heart is overworked; decrease in heart activity so that the supplied O₂ is sufficient for the heart

nadolol and timolol

• both are more potent than propranolol

• timolol tx for chronic open-angle glaucoma

open-angle glaucoma

• iris is in the right position

• ciliary body produces excess liquid that cannot be drained because drainage canals are clogged

• most common form

• develops slowly

B-adrenergic antagonists (topical) that treat for glaucoma

• drugs: betaxolol, carteolol, levobunolol, metipranolol, timolol

• mechanism of action:

  • decrease of aqueous humor production

• side effects:

  • ocular irritation

  • contraindicated in patients w/ asthma, obstructive airway disease, bradycardia, congestive heart failure

a-adrenergic agonists (topical) that treat for glaucoma

• drugs: apraclonidine, brimonidine

• mechanism of action:

  • decrease of aqueous humor production and increase of aqueous flow

• side effects:

  • red eye, ocular irritation, allergic rxns, malaise, headaches

what type of drugs are used for chronic management of glaucoma?

beta blockers

what type of drugs are used for emergency tx of glaucoma?

cholinergic agonists

selective B₁ antagonists

• cardioselective beta blockers

• good selectivity at low doses

• some are more appropriate when used in conjunction w/ other symptoms

• acebutolol

• atenolol

• metoprolol

• bisoprolol

• betaxolol

• esmolol

which B₁ antagonists help treat hypertensive patients w/ impaired pulmonary function?

• acebutolol

• atenolol

• metoprolol

• bisoprolol

• betaxolol

• esmolol

which B₁ antagonists help treat chronic stable angina?

• acebutolol

• atenolol

• metoprolol

• bisoprolol

• betaxolol

• esmolol

which B₁ antagonists help treat heart failure?

• metoprolol

• bisoprolol

acebutolol and pindolol

• beta antagonists w/ partial agonist activity (intrinsic sympathomimetic)

  • occupies receptor and blocks NE from binding to it

• drugs also weakly stimulate both B₁ and B₂ receptors

• fewer effects on lipid and carbohydrate metabolism

• acebutolol→ B₁ selective antagonist

• pindolol→ nonselective B-blocker

• therapeutic uses:

  • B-blockers w/ ISA are effective in hypertensive patients w/ moderate bradycardia→ less pronounced effect on heart

  • B-blockers w/ ISA are not used for stable angina or arrhythmias due to their partial agonist effect

antagonists of a and B adrenoceptors

• labetalol

• carvedilol

• actions:

  • nonselective B-blockers w/ concurrent a₁-blocking actions that produce peripheral vasodilation, thereby reducing BP

  • no initial peripheral vasoconstriction, thus useful in tx hypertensive patients for whom increased peripheral vascular resistance is undesirable

• therapeutic use:

  • labetalol→ alternative to methyldopa in pregnancy-induced HTN, IV infusion for emergencies

  • carvedilol→ beneficial in patients w/ stable chronic HF (blocks effects of sympathetic stimulation on heart)

• adverse effects:

  • orthostatic hypotension, dizziness => a₁ blockade