Adrenergic Antagonists

• These drugs act by either reversibly or irreversibly attaching to the receptor, thus preventing its activation by endogenous catecholamines.

• Adrenergic antagonists are classified according to their relative affinities for α or β receptors in the peripheral nervous system.

α-ADRENERGIC BLOCKING AGENTS

• α adrenoceptors blockers profoundly affect blood pressure. • Decrease in TPR• This induces a reflex tachycardia. • Effects are more profound in an individual who is standing and

less in a person who is supine.

A. Phenoxybenzamine

• Nonselective: α1- and α2-receptors.

• Blocks acetylcholine, histamine, and serotonin receptors

• The block is irreversible and noncompetitive.

• Long-acting: last about 24 hours after a single administration.

1. Actions:

Cardiovascular effects:

Alpha 1 action: – It prevents vasoconstriction of peripheral blood vessels– The decreased peripheral resistance provokes a reflex tachycardia.

Presynaptic α2 receptors in the heart: • increases cardiac output.

• Unsuccessful in maintaining lowered blood pressure in hypertension, and its use has been discontinued for this purpose.

2. Therapeutic uses Phenoxybenzamine:

• Treatment of pheochromocytoma.

• Phenoxybenzamine is sometimes effective in treating Raynaud disease, frostbite, and acrocyanosis.

• Management of autonomic hyperreflexia.

3. Adverse effects of Phenoxybenzamine:

• Postural hypotension• nasal stuffiness• Nausea• Vomiting• It may inhibit ejaculation. • It may induce reflex tachycardia.

B. Phentolamine

• Competitive blocker of α1 and α2 receptors.

• Duration of action: approximately 4 hours

• Potent vasodilator, but induces pronounced reflex tachycardia

• blocking the α2 receptors of the cardiac sympathetic nerves causes cardiac stimulation

• Phentolamine is used for: 1. the short-term management of pheochromocytoma. 2. used locally to prevent dermal necrosis and extravasation

due to norepinephrine administration 3. used to treat hypertensive crisis due to: • abrupt withdrawal of clonidine • from ingesting tyramine-containing foods in patients

taking nonselective monoamine oxidase inhibitors.

C. Selective competitive blockers of the α1 receptor

PrazosinTerazosinDoxazosinTamsulosinAlfuzosin

• Prazosin, terazosin, doxazosin: treatment of hypertension. • Tamsulosin and alfuzosin: treatment of benign prostatic hypertrophy

(BPH).

• Doxazosin is the longest acting of these drugs.

1. Cardiovascular effects: • They decrease peripheral vascular resistance and lower

arterial blood pressure by causing the relaxation of both arterial and venous smooth muscle.

• They cause minimal changes in: – cardiac output– renal blood flow– glomerular filtration rate.

2. Therapeutic uses:

• Treatment of hypertension• The first dose of these drugs produces an exaggerated

orthostatic hypotensive response that can result in syncope (fainting).

• This action, termed a “first-dose” effect, may be minimized by: – adjusting the first dose to one-third or one-fourth of the normal dose – giving the drug at bedtime.

• These drugs improve lipid profiles and glucose metabolism in hypertensive patients.

• Prazosin and others are used to treat congestive heart failure. – By dilating both arteries and veins, these agents decrease

preload and afterload, leading to an increase in cardiac output and a reduction in pulmonary congestion.

• Tamsulosin is an inhibitor (with some selectivity) of the α1A receptors found on the smooth muscle of the prostate.

3. Adverse effects:

• Dizziness• A lack of energy• nasal congestion• Headache• Drowsiness• orthostatic hypotension.

• Prazosin Should be given along with a diuretic : retain sodium (Na+) and fluid.

• Tamsulosin has a caution about “floppy iris syndrome,” a condition in which the iris swells out in response to intraoperative eye surgery.

D. Yohimbine Selective competitive α2 blocker

• It is found as a component of the bark of the yohimbe

• Sometimes used as a sexual stimulant.

• Yohimbine works at the level of the CNS to increase sympathetic outflow to the periphery.

III. β-ADRENERGIC BLOCKING AGENTS

• Competitive antagonists.

• Non-selective: β1 and β2 receptors

• Cardioselective β antagonists primarily block β1 receptors

• β blockers are effective in treating – Angina– cardiac arrhythmias– myocardial infarction– congestive heart failure– Hyperthyroidism– Glaucoma– prophylaxis of migraine

headaches. The names of all β blockers end in “-olol” except for labetalol and carvedilol.

A. Propranolol: prototype β-adrenergic antagonist

• A nonselective β antagonist: blocks both β1 and β2 receptors with equal affinity

• Sustained-release preparations for once-a-day dosing are available.

1. Actions: a) Cardiovascular: – Diminishes cardiac output:• having negative inotropic and chronotropic effects . • It directly depresses sinoatrial and atrioventricular

activity.

b. Peripheral vasoconstriction: • Blockade of β receptors prevents β2-mediated vasodilation. CO BP reflex peripheral vasoconstriction.

• No postural hypotension occurs, because the α1-adrenergic receptors that control vascular resistance are unaffected.

c. Bronchoconstriction: • This can precipitate a

respiratory crisis in patients with chronic obstructive pulmonary disease (COPD) or asthma.

d. Increased Na+ retention: • Reduced blood pressure

causes a decrease in renal perfusion, resulting in an increase in Na+ retention and plasma volume.

• In some cases, this compensatory response tends to elevate the blood pressure. For these patients, β blockers are often combined with a diuretic to prevent Na+ retention

e. Disturbances in glucose metabolism: • β Blockade leads to decreased:

• Glycogenolysis• glucagon secretion.

• Therefore, if a patient with type 1 diabetes is to be given propranolol, very careful monitoring of blood glucose is essential, because pronounced hypoglycemia may occur after insulin injection.

• β Blockers also attenuate the normal physiologic response to hypoglycemia.

• Because of its ability to suppress glycogenolysis and mask tachycardia, propranolol must be used with caution by diabetic patients."

2. Pharmacokinetics:

• After oral administration, propranolol is almost completely absorbed.

• It is subject to first-pass effect, and only about 25 percent of an administered dose reaches the circulation.

• it is highly lipophilic and readily crosses the blood-brain barrier.

• Propranolol is extensively metabolized, and most metabolites are excreted in the urine.

3. Therapeutic effects:

a. Hypertension: • by several different mechanisms of action.

1. Decreased cardiac output is the primary mechanism2. inhibition of renin release from the kidney3. decrease in total peripheral resistance with long term use4. decreased sympathetic outflow from the CNS

b. Migraine: • Propranolol is also

effective in reducing migraine episodes when used prophylactically.

• β Blockers decrease the incidence and severity of the attacks.

c. Hyperthyroidism: • Propranolol and other β

blockers are effective in blunting the widespread sympathetic stimulation that occurs in hyperthyroidism.

• In acute hyperthyroidism (thyroid storm), β blockers may be lifesaving in protecting against serious cardiac arrhythmias.

d. Angina pectoris: • Propranolol decreases the oxygen requirement of heart

muscle and, therefore, is effective in reducing the chest pain on exertion that is common in angina.

• Propranolol is, thus, useful in the chronic management of stable angina but not for acute treatment.

e. Myocardial infarction: • Administration of a β blocker immediately following a

myocardial infarction reduces infarct size and hastens recovery.

• Used prophylactically after an MI.– Protective effect on the myocardium: blocking of the

actions of circulating catecholamines, which would increase the oxygen demand in an already ischemic heart muscle.

– Propranolol also reduces the incidence of sudden arrhythmic death after myocardial infarction.

4. Adverse effects:

The reasons for this are not clear and may be independent of β-receptor blockade.

The β blockers must be tapered of gradually for at least a few weeks.

Metabolic disturbances: • β Blockade: decreases glycogenolysis and glucagon secretion. • Fasting hypoglycemia may occur. • In addition, β blockers can prevent the counter regulatory

effects of catecholamines during hypoglycemia. • The perception of symptoms such as tremor, tachycardia, and

nervousness are blunted.

• Patients administered nonselective β blockers have: – increased low-density lipoprotein– increased triglycerides– reduced high-density lipoprotein

e. CNS effects:

• Propranolol has numerous CNS-mediated effects, including: – Depression– Dizziness– Lethargy– Fatigue– Weakness

• visual disturbances• Hallucinations• short-term memory loss• emotional liability• vivid dreams (including

nightmares)• decreased performance• insomnia.

f. Drug interactions:

• Drugs that interfere with, or inhibit, the metabolism of propranolol, such as cimetidine, fluoxetine, paroxetine, and ritonavir, may potentiate its antihypertensive effects.

• Conversely, those that stimulate or induce its metabolism, such as barbiturates, phenytoin, and rifampin, can decrease its effects.

B. Timolol and nadolol: Nonselective β antagonists

• More potent than propranolol.

• Nadolol has a very long duration of action.

• Timolol reduces the production of aqueous humor in the eye.

• It is used topically in the treatment of chronic open-angle glaucoma.

1. Treatment of glaucoma:

• Topically applied agents: timolol, betaxolol, or carteolol

• They decrease the secretion of aqueous humor by the ciliary body.

• Chronic use : The β blockers• Acute attack of glaucoma: pilocarpine is the drug of choice.

• Onset: 30 minutes• Duration of action: 12 to 24 hours.

C. Selective β1 antagonists:

• Acebutolol• Atenolol• Metoprolol• Bisoprolol• Betaxolol• Nebivolol• Esmolol

• This cardio selectivity is: – most pronounced at

low doses– lost at high doses

1. Actions:

• These drugs: – lower blood pressure in

hypertension– increase exercise

tolerance in angina.

• Esmolol has a very short lifetime ( 10 min.) due to metabolism of an ester linkage.

• Nebivolol also has vasodilator properties mediated by nitric oxide.

2. Therapeutic use in hypertension:

A. The cardioselective β blockers are useful in hypertensive patients with impaired pulmonary function. – Because these drugs have less effect on peripheral

vascular β2 receptors.

B. Cardioselective β blockers are useful in diabetic hypertensive patients.

D. Antagonists with partial agonist activity: Pindolol and acebutolol

1. Actions: A. Cardiovascular: • They are not pure

antagonists, they are partial agonists.• They have intrinsic

sympathomimetic activity (ISA).

B. Decreased metabolic effects:

– Minimal effect on lipid and carbohydrate metabolism.

– For example, these agents do not decrease plasma HDL levels.

2. Therapeutic use in hypertension:

1. Hypertensive patients with moderate bradycardia: because a further decrease in heart rate is less pronounced with these drugs.

2. Diabetic hypertensive patients: carbohydrate metabolism is less affected.

E. Antagonists of both α and β adrenoceptors: Labetalol and carvedilol

1. Actions: • α1-blocking actions: produce

peripheral vasodilation, thereby reducing blood pressure.

• They do not alter serum lipid or blood glucose levels.

• Carvedilol also decreases lipid peroxidation and vascular wall thickening, effects that have benefit in heart failure.

2. Therapeutic use in:1. hypertension2. heart failure

• Labetalol may be used as: – an alternative to

methyldopa in the treatment of pregnancy-induced hypertension.

– Intravenously to treat hypertensive emergencies, because it can rapidly lower blood pressure.

• Carvedilol:– Clinical trials have shown

that carvedilol has clinical benefits in patients with stable chronic heart failure.

– It can reduce mortality and hospitalization in this population.

3. Adverse effects: associated with α1 blockade

• Orthostatic hypotension• Dizziness.

IV. DRUGS AFFECTING NEUROTRANSMITTER RELEASE OR UPTAKE

These agents are seldom used therapeutically.

A. Reserpine

• Reserpine, a plant alkaloid, blocks the Mg2+/ATP–dependent transport of biogenic amines, norepinephrine, dopamine, and serotonin from the cytoplasm into storage vesicles in the adrenergic nerves of all body tissues.

• This causes the ultimate depletion of biogenic amines.

• Sympathetic function, in general, is impaired because of decreased release of norepinephrine.

• The drug has a slow onset• Has a long duration of

action• effects that persist for

many days after discontinuation.

B. Guanethidine

• Guanethidine blocks the release of stored norepinephrine as well as displaces norepinephrine from storage vesicles (thus producing a transient increase in blood pressure).

• This leads to gradual depletion of norepinephrine in nerve endings except for those in the CNS.

• Guanethidine commonly causes orthostatic hypotension and interferes with male sexual function.

• Supersensitivity to norepinephrine due to depletion of the amine can result in hypertensive crisis in patients with pheochromocytoma.

C. Cocaine

• Mechanism of action: blockade of reuptake of the monoamines (norepinephrine, serotonin, and dopamine) into the presynaptic terminals from which these neurotransmitters are released.

• This blockade potentiates and prolongs the CNS and peripheral actions of these monoamines.

• The prolongation of dopaminergic effects in the brain’s pleasure system (limbic system) produces the intense euphoria that cocaine initially causes.

• Chronic intake of cocaine depletes dopamine.

• This depletion triggers craving for cocaine.