β-Adrenergic Blockers

Dr. Hiwa K. SaaedPh.D. Pharmacology

& Toxicology

β-Adrenergic Blockersβ-Blockers are effective in treating :• angina, • cardiac arrhythmias, • myocardial infarction, • congestive heart failure, • hyperthyroidism, • and glaucoma, • prophylaxis of migraine headaches.

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

β-Blockers

• All are competitive antagonists• Propranolol is prototype

• Although all β-blockers lower blood pressure in hypertension, they do not induce postural hypotension,

• because the α-adrenoceptors remain functional.

A. Classification and MechanismsSelectivity (β1>β2)

Partial agonist activity (Intrinsic Sympathomimetic Activity “ISA”)

Lipid solubility (CNS effect)Membrane stabilizing activity

(MSA)(local anesthetic action) Capacity to block alpha

adrenoceptors.K+ channel blockade (sotalol)

A. Classification: Selectivity (β1>β2)

• β1 selective (cardioselective)• Atenolol• Acebutolol• Bisoprolol• Esmolol (short t1/2)• MetoplrololAdvantage: HTN with asthma,

peripheral vascular disease (coldness of extremities), NIDDM

A. Classification and Mechanisms

Selective β2 • Butoxamine (experimental)Nonselective (β1 & β2)• Nadolol• Propranolol• Timolol

Combined (α & β): peripheral vasodilation

• Labetalol• Carvedilol• Useful in Rx HTN patients for whom increased

Peripheral resistance is undesirable (elderly or black)

• Labetalol in Rx preeclampsia, pheochromocytoma

• They do not alter serum lipid or blood glucose levels

• Carvedilol also decreasees lipid peroxidation and vascular wall thickening (benefit in heart failure)

Partial agonist activity ISA• Pindolol• Acebutolol• Labetalolless bradycardia & diminished effect on

COP, less disturbances of lipid and carbohydrate

metabolismAdvantages: • HTN with asthma, • HTN with moderate bradycardia • HTN+DM

A. Classification and Mechanisms3. Local anesthetic activity

(membrane-stabilizing activity):–Is a disadvantage when used topically in the eye because it decreases protective reflexes and increases the risk of corneal ulceration

–Timolol, atenolol, carvedilol &nadolol: no Local anesthetic activity

4. Lipid solubility–responsible for CNS adverse effects: propranolol

Lipid soluble

Pharmacokinetic properties

Water soluble

Pharmacokinetic properties

Propranolol

Highly metabolizedLarge VdCNS penetration Shorter t1/2

Acebutolol

Excreted unchanged by kidneyLess 1st pass effectSmall VdLonger t1/2 except esmolol

Timolol

Atenolol

Pindolol

Esmolol

Metoprolol

Nadolol

Labetalol

K+ channel blockade: sotalol

• Sotalol is a nonselective β receptor antagonists,

• that lack LA action • but has marked class III

antiarrhythmia effect reflecting k+ channel blockade

B. Pharmacological Effects and Clinical Uses

1. CVS: A. Heart: both

–decreased HR, force of contraction (–ve inotropic & chronotropic effect)

–decreased A-V conduction, ↑PR interval

–Decrease CO, work & O2 consumption

Rx: Angina and Supraventricular tachycardia

Reflex peripheral vasoconstriction!?

B. Vascular system: prevent β2 mediated vasodilation→ reduction in COP (because of cardiac effect) → decrease BP → reflex vasoconstriction.

• On balance there is gradual reduction of both systolic and diastolic BP

2. Respiratory: bronchoconstriction; contraindicated in asthma

3. Eye: reduce IOP especially in Glaucomatous eyes decrease aqueous humor production

B. Pharmacological Effects and Clinical Uses

4. metabolic and endocrine effects: A. Increased Na+ retention, how?– Reduced blood pressure causes a

decrease in renal perfusion, resulting in an increase in Na+ retention and ↑plasma volume→

– In some cases, ↑blood pressure.– For these patients, β-blockers are often

combined with a diuretic to prevent Na+ retention.

– Also by inhibiting β receptors, renin production is also prevented, contributing to Na+ retention.

B. Pharmacological Effects and Clinical Uses

B. inhibit lipolysis: ↑ plasma VLDL, ↓ HDL, ─LDL

↓ HDL/LDL ratio→ coronary heart disease

C. partially inhibit glycogenolysis and decrease glucagon secretion

• Great caution in IDDM (Type 1)?• Because pronounce hypoglycemia

may occur after insulin injection, β blockers also attenuate the normal physiologic response to hypoglycemia, furthermore they mask signs of hypoglycemia; tremor, palpitation..

B. Pharmacological Effects and Clinical Uses

B. Clinical UsesCardiovascular and ophthalmic

applications are extremly importantA. CVS:

-angina pectoris ↓cardiac work & O2

demand, -Chronic hypertension, ↓CO, ↓ TPR,

inhibition of renin releaseNB: β blockers are not used for acute or emergency Rx of HTN,? ma y

increase diastolic pressure

Labetalol is effective in emergency

-Arrhythmia (supraventricular tachycardias),

-prophylaxis after MI: 1) early use within 6-12 hrs for

3-4 wks2) Late use within 4 days- 4 wks

after onset of infarction and continued for at least 2 years useful for secondary prevention from another MI

- congestive heart failure*

B. Clinical Uses

B. Eye: Glaucoma: reduce aqueous humor secretion (timolol)

C. Endocrine use: Thyroid storm, thyrotoxicosis: propranolol

D. CNS: propranolol 1. Anxiety with somatic symptoms2. Migraine headache prophylaxis:3. Famillial tremor, other types of

tremor, “stage fright”:

4. Alcohol, opioids acute withdrawal symptoms

B. Clinical Uses

C. Adverse effects

• CVS: bradycardia, A-V blockade, CHF

• Arrhythmias: never stop Rx with β blockers suddenly

• Bronchoconstriction: Patients with airway disease: asthmatic attack

• Sexual dysfunction?? Indep of β blockade

• CNS effects: sedation, fatigue, sleep alterations

Thank You